Intranasal epinephrine formulations and methods for the treatment of disease

ABSTRACT

Drug products adapted for nasal delivery comprising formulations with epinephrine and devices comprising such formulations are provided. Methods of treating anaphylaxis with epinephrine products are also provided.

CROSS REFERENCE

This application is a continuation of U.S. patent application Ser. No.18/049,936, filed Oct. 26, 2022, which is a continuation of U.S. patentapplication Ser. No. 17/369,044, filed Aug. 6, 2021, which is acontinuation of U.S. patent application Ser. No. 16/869,461 filed May 7,2020, now U.S. Pat. No. 11,191,838, issued Dec. 7, 2021, which is acontinuation of U.S. patent application Ser. No. 16/420,044 filed on May22, 2019, now U.S. Pat. No. 10,682,414 issued Jun. 16, 2020, which is acontinuation of International Application No. PCT/US2019/016918 filed onFeb. 6, 2019, which claims the benefit of U.S. Provisional PatentApplication No. 62/784,057 filed on Dec. 21, 2018; each of which isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

Described herein are intranasal (IN) epinephrine formulations andmethods of using such formulations in the treatment of conditions ordiseases.

BACKGROUND OF THE INVENTION

Anaphylaxis is a medical emergency that may require resuscitationmeasures such as airway management, supplemental oxygen, large volumesof intravenous fluids, and close monitoring. Administration ofepinephrine is the treatment of choice. A need exists for needle-freeand non-invasive methods of dosing epinephrine. Provided herein aremethods, formulations, and devices for the treatment of anaphylaxis andother conditions.

SUMMARY OF THE INVENTION

Disclosed herein are methods, pharmaceutical formulations of epinephrineand methods of use thereof in the treatment of conditions such as type-1hypersensitivity reactions (systemic allergic reaction), asthma, andcardiac arrest.

Anaphylaxis is a severe, potentially life-threatening type-1hypersensitivity reaction (systemic allergic reaction) that affects manybody systems, with rapid onset typically averaging between about 5 to 30minutes after intravenous exposure to an antigen and about 2 hours afteroral exposure. Anaphylaxis results from the release of inflammatorymediators and cytokines from mast cells and basophils, typically due toan immunologic reaction, but sometimes due to non-immunologicmechanisms. The most common areas of the body affected include: skin(80-90%), respiratory (70%), gastrointestinal (30-45%), heart andvasculature (10-45%), and central nervous system (10-15%) with usuallytwo or more being involved in a single episode.

Anaphylaxis is a medical emergency that may require resuscitationmeasures such as airway management, supplemental oxygen, large volumesof intravenous fluids, and close monitoring. Administration ofepinephrine is the treatment of choice with antihistamines and steroids(for example, dexamethasone) often used as adjuncts. Due to concerns ofbiphasic anaphylaxis, a period of in-hospital observation for between 2and 24 hours is often required for people once they have returned tonormal.

Epinephrine (adrenaline,(R)-4-(1-Hydroxy-2-(methylamino)ethyl)benzene-1,2-diol) is the primarytreatment for anaphylaxis with no absolute contraindication to its use.Currently epinephrine is administered as a solution given by injection,preferably into the mid anterolateral thigh as soon as anaphylaxis issuspected. The injection may be repeated every 5 to 15 minutes if thereis insufficient response. A second dose is needed in 16-35% of episodes,but more than two doses are rarely required. The intramuscular route ispreferred over subcutaneous administration because the latter may havedelayed epinephrine absorption. However, while only minor adverseeffects from epinephrine are reported (tremors, anxiety, headaches, andpalpitations) there have been numerous reports of the highly variableexposures from injection products depending on the location of theinjection (intramuscular or subcutaneous), and other factors such asbody mass index (BMI).

There is a significant need in the medical community to develop productsthat will help improve the clinical management of anaphylaxis in anout-of-hospital setting. While epinephrine is effective when deliveredby intramuscular injection, there is published evidence that thepharmacokinetics are highly variable depending on the site of theinjection, whether intramuscular or subcutaneous. There have also beensignificant product quality problems with approved auto-injectors thatutilize complex technologies, resulting in many recalls for theseproducts by the FDA in the United States. Epinephrine auto-injectors,such as EpiPen®, are also cumbersome to carry, and require training andtime to properly administer in a potentially life-threatening situation.

The need for alternative, needle-free and non-invasive methods fordosing epinephrine are well-documented, as many patients have a fear ofinjection and, as a result, are reluctant to use an auto-injector of anykind. Further, the auto-injectors are large and burdensome, so manypatients in need do not have an epinephrine injector in their presenceat all times. There is also a well-documented reluctance toself-administer a dose in public settings.

Thus, there is a need for improved or alternative methods of dosingepinephrine in an emergency situation, as well as improved oralternative formulations and devices. Desirable improvements include:individually and in combinations, convenience (intranasal versusintramuscular), more rapid administration, more reliable, moreconsistent dosing, needleless, more discrete to dose in public, andadministrable by an untrained individual or non-professional.

Accordingly, provided herein are methods, formulations, and devices forthe treatment of anaphylaxis and other conditions comprisingadministering an intranasal formulation of epinephrine using a smallcompact unit dose sprayer device.

In one aspect, described herein is a nasal spray pharmaceuticalformulation comprising between about 0.40 mg and about 2.4 mg ofepinephrine, or a salt thereof. In another aspect, described herein is anasal spray pharmaceutical formulation comprising between about 0.40 mgand about 2.4 mg of epinephrine, or a salt thereof, in a single dose ofthe nasal spray pharmaceutical formulation. In another aspect, describedherein is a nasal spray pharmaceutical formulation comprising betweenabout 0.40 mg and about 2.4 mg of epinephrine, or a salt thereof, in asingle dose nasal spray pharmaceutical formulation. In some embodiments,the nasal spray pharmaceutical formulation comprises between about 0.40mg and about 2.0 mg of epinephrine, or a salt thereof. In someembodiments, the nasal spray pharmaceutical formulation comprisesbetween about 0.40 mg and about 1.8 mg of epinephrine, or a saltthereof. In some embodiments, a single dose of the nasal spraypharmaceutical formulation comprises between about 0.5 mg and about 2.0mg of epinephrine, or a salt thereof. In some embodiments, a single doseof the nasal spray pharmaceutical formulation comprises between about0.5 mg and about 1.5 mg of epinephrine, or a salt thereof. In someembodiments, a single dose of the nasal spray pharmaceutical formulationcomprises between about about 0.5 mg and about 0.7 mg of epinephrine, ora salt thereof. In some embodiments, a single dose of the nasal spraypharmaceutical formulation comprises about 1.0 mg of epinephrine, or asalt thereof. In some embodiments, a single dose of the nasal spraypharmaceutical formulation comprises between about 1.3 mg and about 1.5mg of epinephrine, or a salt thereof. In some embodiments, intranasaladministration of a single dose of the nasal spray pharmaceuticalformulation to a subject provides a plasma epinephrine concentrationthat are efficacious for the treatment of an acute hypersensitivityreaction. In some embodiments, the nasal spray pharmaceuticalformulation is an aqueous solution, aqueous suspension, aqueousemulsion, non-aqueous solution, non-aqueous suspensions, non-aqueousemulsion, or dry powder.

In one aspect, described herein is a nasal spray formulation comprisingbetween about 0.40 mg and about 2.4 mg per dose of epinephrine, or asalt thereof, dispensed from the device. In some embodiments, describedherein is a nasal spray formulation comprising between about 0.5 mg andabout 2.0 mg of epinephrine, or a salt thereof, per dose dispensed fromthe device; between about 0.5 mg and about 1.5 mg of epinephrine, or asalt thereof, per dose dispensed from the device; between about 0.5 mgand about 0.7 mg of epinephrine, or a salt thereof, per dose dispensedfrom the device; about 1.0 mg of epinephrine, or a salt thereof, perdose dispensed from the device; or between about 1.3 mg and about 1.5 mgof epinephrine, or a salt thereof, per dose dispensed from the device.In some embodiments, a single dose of the the nasal spray formulationwhen administered intranasally provides plasma epinephrineconcentrations that are efficacious for the treatment of an acutehypersensitivity reaction. In some embodiments, the epinephrine or saltthereof is present in the pharmaceutical formulation in an amountefficacious for the treatment of an acute hypersensitivity reaction. Insome embodiments, the nasal spray formulation is an aqueous solution,aqueous suspension, aqueous emulsion, non-aqueous solution, non-aqueoussuspension or non-aqueous emulsion.

In some embodiments, the nasal spray formulation comprises between about1 mg/mL and about 40 mg/mL of epinephrine, or a salt thereof, per dose.In some embodiments, the nasal spray formulation comprises between about5 mg/mL and about 40 mg/mL of epinephrine, or a salt thereof, per dose.In some embodiments, the nasal spray formulation comprises between about1 mg/mL and about 20 mg/mL of epinephrine, or a salt thereof, per dose.In some embodiments, the nasal spray formulation comprises between about3 mg/mL and about 20 mg/mL of epinephrine, or a salt thereof, per dose.In some embodiments, the nasal spray formulation comprises between about3 mg/mL and about 15 mg/mL of epinephrine, or a salt thereof, per dose.In some embodiments, the nasal spray formulation comprises about 3mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL,about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17mg/mL, about 18 mg/mL, about 19 mg/mL, or about 20 mg/mL of epinephrine,or a salt thereof, per dose. In some embodiments, a dose of the nasalspray formulation comprises about 100 μL of the nasal spray epinephrineformulation described herein.

In some embodiments, a nasal spray formulation described hereincomprises about 1 mg/mL to about 40 mg/mL of epinephrine, or a saltthereof. In some embodiments, a nasal spray formulation described hereincomprises about 1 mg/mL to about 20 mg/mL of epinephrine, or a saltthereof. In some embodiments, a nasal spray formulation described hereincomprises about 1 mg/mL to about 18 mg/mL of epinephrine, or a saltthereof. In some embodiments, a nasal spray formulation described hereincomprises about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL,about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL, about 13 mg/mL,about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18mg/mL, about 19 mg/mL, or about 20 mg/mL of epinephrine, or a saltthereof. In some embodiments, a nasal spray formulation described hereincomprises about about 3 mg/mL, about 5 mg/mL, about 6 mg/mL, about 6.5mg/mL, about 7 mg/mL, about 7.5 mg/mL, about 8 mg/mL, about 8.5 mg/mL,about 9 mg/mL, about 9.5 mg/mL, about 10 mg/mL, about 10.5 mg/mL, about11 mg/mL, about 11.5 mg/mL, about 12 mg/mL, about 12.5 mg/mL, about 13mg/mL, about 13.5 mg/mL, about 14 mg/mL, about 14.5 mg/mL, or about 15mg/mL of epinephrine, or a salt thereof. In some embodiments, a nasalspray formulation described herein comprises about about 10 mg/mL ofepinephrine, or a salt thereof. In some embodiments, a nasal sprayformulation described herein comprises about 6 mg/mL to about 8 mg/mL ofepinephrine, or a salt thereof. In some embodiments, a nasal sprayformulation described herein comprises about 13 mg/mL to about 15 mg/mLof epinephrine, or a salt thereof. In some embodiments, a dose of thenasal spray formulation comprises about 100 μL of the nasal sprayepinephrine formulation described herein.

In some embodiments, a dose of about 100 μL of the nasal sprayformulation described herein comprises 1 mg/mL to about 40 mg/mL ofepinephrine, or a salt thereof. In some embodiments, a dose of about 100μL of the nasal spray formulation described herein comprises 1 mg/mL to20 mg/mL of epinephrine, or a salt thereof. In some embodiments, a doseof about 100 μL of the nasal spray formulation described hereincomprises 3 mg/mL, 3.5 mg/mL, 4 mg/mL, 4.5 mg/mL, 5 mg/mL, 6 mg/mL, 6.5mg/mL, 7 mg/mL, 7.5 mg/mL, 8 mg/mL, 8.5 mg/mL, 9 mg/mL, 9.5 mg/mL, 10mg/mL, 10.5 mg/mL, 11 mg/mL, 11.5 mg/mL, 12 mg/mL, 12.5 mg/mL, 13 mg/mL,13.5 mg/mL, 14 mg/mL, 14.5 mg/mL, or 15 mg/mL of epinephrine, or a saltthereof.

In some embodiments, the nasal spray formulation comprises one or moreabsorption enhancers.

In some embodiments, the nasal spray formulation provides intramuscular(IM)-injection-like pharmacokinetics when IM-injection is dosed in thelateral thigh, or subcutaneous (SC)-like absorption or in between.

In some embodiments, the nasal spray formulation provides intramuscular(IM)-injection-like absorption.

In some embodiments, the nasal spray formulation provides subcutaneous(SC)-like absorption and the SC pharmacokinetic profile has a C_(max) ofat least 100 pg/mL and AUC_(0-240 min) of 150 h*pg/mL.

In some embodiments, intranasal administration of a single dose of thenasal spray pharmaceutical formulation to a subject providesintramuscular (IM)-injection-like absorption.

In some embodiments, the nasal spray formulation when administered to asubject yields one or more of the following pharmacokinetic features:both the mean AUC_(0-20 min) and AUC_(0-t) are at least 80% of theAUC_(0-20 min) and AUC_(0-t) that a 0.3 mg intramuscular injectionyields; a mean C_(max) that is at least 80% of the C_(max) and no morethan 150% of the C_(max) that a 0.3 mg intramuscular injection yields; amean t_(max) of less than 45 minutes; or IM-injection like absorptionunder optimal dosing conditions in the thigh. In some embodiments, thenasal spray formulation when administered to a subject yields one ormore of the following pharmacokinetic features: both the meanAUC_(0-20 min) and AUC_(0-t) are at least 80% of the AUC_(0-20 min) andAUC_(0-t) that a 0.3 mg intramuscular injection yields; a mean C_(max)that is at least 80% of the C_(max) and no more than 150% of the C_(max)that a 0.3 mg intramuscular injection yields; a mean t_(max) of lessthan 45 minutes; and IM-injection like absorption under optimal dosingconditions in the thigh.

In some embodiments, the nasal spray formulation when administered to asubject yields one or more of the following pharmacokinetic features:both the mean AUC_(0-20 min) and AUC_(0-t) are at least 80% of theAUC_(0-20 min) and AUC_(0-t) that a 0.15 mg intramuscular injectionyields; a mean C_(max) that is at least 80% of the C_(max) and no morethan 150% of the C_(max) that a 0.15 mg intramuscular injection yields;a mean t_(max) of less than 45 minutes; or IM-injection like absorptionunder optimal dosing conditions in the thigh. In some embodiments, thenasal spray formulation when administered to a subject yields one ormore of the following pharmacokinetic features: both the meanAUC_(0-20 min) and AUC_(0-t) are at least 80% of the AUC_(0-20 min) andAUC_(0-t) that a 0.15 mg intramuscular injection yields; a mean C_(max)that is at least 80% of the C_(max) and no more than 150% of the C_(max)that a 0.15 mg intramuscular injection yields; a mean t_(max) of lessthan 45 minutes; and IM-injection like absorption under optimal dosingconditions in the thigh.

In some embodiments, the nasal spray formulation when administered to asubject yields one or more of the following pharmacokinetic features:both the mean AUC_(0-20 min) and AUC_(0-t) are at least 80% of theAUC_(0-20 min) and AUC_(0-t) that a 0.5 mg intramuscular injectionyields; a mean C_(max) that is at least 80% of the C_(max) and no morethan 150% of the C_(max) that a 0.5 mg intramuscular injection yields; amean t_(max) of less than 45 minutes; or IM-injection like absorptionunder optimal dosing conditions in the thigh. In some embodiments, thenasal spray formulation when administered to a subject yields one ormore of the following pharmacokinetic features: both the meanAUC_(0-20 min) and AUC_(0-t) are at least 80% of the AUC_(0-20 min) andAUC_(0-t) that a 0.5 mg intramuscular injection yields; a mean C_(max)that is at least 80% of the C_(max) and no more than 150% of the C_(max)that a 0.5 mg intramuscular injection yields; a mean t_(max) of lessthan 45 minutes; and IM-injection like absorption under optimal dosingconditions in the thigh.

In some embodiments, the nasal spray formulation comprises between about0.5 and about 1.1 molar equivalents of acid to each mole of epinephrine.In some embodiments, the acid is adipic acid, ammonium chloride, citricacid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid,propionic acid, sulfuric acid or tartaric acid. In some embodiments, theacid is hydrochloric acid. In some embodiments, no base is added to thenasal spray formulation during its preparation. In some embodiments, thenasal spray formulation has a pH between about 2.0 and about 6.0. Insome embodiments, the nasal spray formulation has a pH of about 4.0.

In some embodiments, the nasal spray formulation comprises between about5 mg/mL and about 40 mg/mL per dose epinephrine, or a salt thereof. Insome embodiments, the nasal spray formulation comprises between about0.9 mg and about 2.40 mg per dose dispensed from the device ofepinephrine, or a salt thereof. In some embodiments, the nasal sprayformulation comprises between about 0.5 mg and about 2.0 mg per dosedispensed from the device of epinephrine, or a salt thereof. In someembodiments, the nasal spray formulation comprises between about 0.9 mgand about 1.5 mg per dose dispensed from the device of epinephrine, or asalt thereof. In some embodiments, the nasal spray formulation comprisesbetween about 0.75 mg and about 1.5 mg per dose dispensed from thedevice of epinephrine, or a salt thereof. In some embodiments, the nasalspray formulation comprises between about 0.45 mg and about 1.15 mg perdose dispensed from the device of epinephrine, or a salt thereof. Insome embodiments, the nasal spray formulation comprises between about1.0 mg and about 2.0 mg per dose dispensed from the device ofepinephrine, or a salt thereof. In some embodiments, the nasal sprayformulation comprises between about 0.5 mg and about 2.0 mg ofepinephrine, or a salt thereof, per dose dispensed from the device. Insome embodiments, the nasal spray formulation comprises between about0.5 mg and about 1.5 mg of epinephrine, or a salt thereof, per dosedispensed from the device. In some embodiments, the nasal sprayformulation comprises between about 0.5 mg and about 0.7 mg ofepinephrine, or a salt thereof, per dose dispensed from the device. Insome embodiments, the nasal spray formulation comprises about 1.0 mg ofepinephrine, or a salt thereof, per dose dispensed from the device. Insome embodiments, the nasal spray formulation comprises between about1.3 mg and about 1.5 mg of epinephrine, or a salt thereof, per dosedispensed from the device.

In some embodiments, the nasal spray pharmaceutical formulationcomprises one or more absorption enhancement agents; and optionally oneor more agents selected from isotonicity agents; stabilizing agents;preservatives; taste-masking agents; viscosity modifiers; antioxidants;buffers and pH adjustment agents; wherein the pH of the nasal spraypharmaceutical formulation is between about 2.0 and about 6.0.

In some embodiments, the nasal spray pharmaceutical formulation has a pHbetween about 3.0 and about 5.0. In some embodiments, the nasal spraypharmaceutical formulation has a pH of about 4.0. In some embodiments,the nasal spray pharmaceutical formulation comprises pH adjustmentagents. In some embodiments, the pH adjustment agent is an acid, a base,a buffer, or a combination thereof. In some embodiments, the acid isadipic acid, ammonium chloride, citric acid, acetic acid, hydrochloricacid, lactic acid, phosphoric acid, propionic acid, sulfuric acid ortartaric acid; the base is sodium hydroxide, sodium citrate, sodiumbicarbonate, sodium carbonate; and the buffer is a phosphate buffer,acetate buffer, or citrate buffer. In some embodiments, the nasal spraypharmaceutical formulation comprises between about 0.5 and about 1.1molar equivalents of acid to each mole of epinephrine. In someembodiments, the acid is hydrochloric acid.

In some embodiments, the nasal spray formulation comprises one or moreabsorption enhancers selected from dodecyl maltoside, benzalkoniumchloride, oleic acid, or salt thereof, polysorbate 20, polysorbate 80,and sodium lauryl sulfate.

In some embodiments, the formulation comprises one or more absorptionenhancers selected from alcohol, aprotinin, benzalkonium chloride,benzyl alcohol, capric acid, ceramides, cetylpyridinium chloride,chitosan, cyclodextrins, deoxycholic acid, decanoyl, dimethyl sulfoxide,glyceryl monooleate, glycofurol, glycofurol, glycosylated sphingosines,glycyrrhetinic acids, 2-hydroxypropyl-β-cyclodextrin, laureth-9, lauricacid, lauroyl carnitine, lysophosphatidylcholine, menthol, poloxamer 407or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, isopropylmyristate, isopropyl palmitate, lanolin, light mineral oil, linoleicacid, menthol, myristic acid, myristyl alcohol, oleic acid, or saltthereof, oleyl alcohol, palmitic acid, polysorbate 20, polysorbate 80,propylene glycol, polyoxyethylene alkyl ethers, polyoxylglycerides,pyrrolidone, quillaia saponin, salicylic acid, sodium salt, β-sitosterolβ-D-glucoside, sodium lauryl sulfate, sucrose cocoate, taurocholic acid,taurodeoxycholic acid, taurodihydrofusidic acid, thymol, tricaprylin,triolein, and alkylsaccharides.

In some embodiments, the formulation comprises one or more absorptionenhancers selected from dodecyl maltoside, benzalkonium chloride, oleicacid, or salt thereof, polysorbate 20, polysorbate 80, and sodium laurylsulfate.

In some embodiments, the one or more absorption enhancers are: about0.005% (w/v) to about 2.5% (w/v) dodecyl maltoside; or about 0.001 (w/v)to about 1% (w/v) benzalkonium chloride; or about 0.001 (w/v) to about1% (w/v) oleic acid, or salt thereof or a combination of about about0.005% (w/v) to about 2.5% (w/v) dodecyl maltoside and about 0.001 (w/v)to about 1% (w/v) benzalkonium chloride; or a combination of about about0.005% (w/v) to about 2.5% (w/v) dodecyl maltoside and about 0.001 (w/v)to about 1% (w/v) oleic acid, or salt thereof or a combination of about0.001 (w/v) to about 1% (w/v) benzalkonium chloride and about 0.001(w/v) to about 1% (w/v) oleic acid, or salt thereof.

In some embodiments, the one or more absorption enhancers are: about0.005% (w/v) to about 0.08% (w/v) benzalkonium chloride; or about 0.01%(w/v) to about 0.06% (w/v) benzalkonium chloride; or about 0.01% (w/v)to about 0.04% (w/v) benzalkonium chloride; wherein the benzalkoniumchloride is the sole absorption enhancement agent in the formulation oris in present in the formulation with one or more additional absorptionenhancement agents.

In some embodiments, the formulation comprises a preservative. In someembodiments, the preservative is benzalkonium chloride.

In some embodiments, the nasal spray pharmaceutical formulationcomprises an isotonicity agent. In some embodiments, the isotonicityagent is dextrose, glycerin, mannitol, potassium chloride, or sodiumchloride. In some embodiments, the isotonicity agent is sodium chloride.

In some embodiments, the nasal spray formulation additionally comprisesa stabilizing agent. In some embodiments, the stabilizing agent isethylenediaminetetraacetic acid (EDTA) or a salt thereof. In someembodiments, the EDTA is disodium EDTA. In some embodiments, the nasalspray formulation comprises from about 0.001% (w/v) to about 1% (w/v) ofdisodium EDTA.

In some embodiments, the nasal spray formulation additionally comprisesa preservative. In some embodiments, the preservative is benzalkoniumchloride.

In some embodiments, the nasal spray formulation comprises one or moreabsorption enhancers selected from alkylglycosides, benzalkoniumchloride, oleic acid, or salt thereof, polysorbate 20, polysorbate 80,sodium lauryl sulfate, cyclodextrins, medium and long chain fatty acids,or salts thereof, saturated and unsaturated fatty acids, or saltsthereof, alcohol, glycerin, propylene glycol, PEG 300/400, and benzylalcohol.

In some embodiments, the nasal spray formulation further comprises anantioxidant. In some embodiments, the nasal spray formulation furthercomprises an antioxidant selected from alpha tocopherol, arachidonicacid, ascorbic acid, ascorbyl palmitate, benzethonium chloride,benzethonium bromide, benzalkonium chloride, butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), capric acid, caproic acid, carbondioxide, cetylpyridium chloride, chelating agents, chitosan derivatives,citric acid monohydrate, dodecyl dimethyl aminopropionate, enanthicacid, erythorbic acid, ethyl oleate, fumaric acid, glycerol oleate,glyceryl monostearate, lauric acid, limonene, linolenic acid, lysine,malic acid, menthol, methionine, monothioglycerol, myristic acid, oleicacid, palmitic acid, pelargonic acid, peppermint oil, phosphoric acid,polysorbates, potassium metabisulfite, propionic acid, propyl gallate,sodium ascorbate, sodium bisulfate, sodium caprate, sodiumdesoxycholate, sodium deoxyglycolate, sodium formaldehyde sulfoxylate,sodium glycocholate, sodium hydroxybenzoyal amino caprylate, sodiumlauryl sulfate, sodium metabisulfite, sodium sulfite, sodiumtaurocholate, sodium thiosulfate, stearic acid, sulfur dioxide and acombination thereof.

In some embodiments, the nasal spray formulation further comprisessynergists with the antioxidants selected from citric acid monohydrate,tartaric acid, thymol, tocopherol (alpha tocopherol), tocopherasol,vitamin E and vitamin E polyethylene glycol succinate and a combinationthereof.

In some embodiments, the nasal spray formulation further comprisespermeation enhancers selected from alcohol, arachidonic acid,benzethonium chloride, benzethonium bromide, benzalkonium chloride,capric acid, caproic acid, carvone, cetylpyridium chloride, chitosans,citric acid, 6-cyclohexyl-1-hexyl-β-D-maltopyranoside,n-decyl-β-D-maltopyranoside, dimethyl sulfoxide, dodecyl dimethylaminopropionate, 1-O-n-Dodecyl-β-D-maltopyranoside,dodecylpolyethyleneglycolether, edetate disodium dihydrate, enanthicacid, glyceryl monooleate, glyceryl monostearate, glycofurol, isopropylmyristate, isopropyl palmitate, pelargonic acid, lanolin, lauric acid,light mineral oil, limonene, linoleic acid, lysine, menthol, myristicacid, myristyl alcohol, oleic acid, oleyl alcohol, palmitic acid,peppermint oil, polyoxyethylene alkyl ethers, polyoxylglycerides,polysorbates, pyrrolidone, sodium caprate, sodium desoxycholate, sodiumdeoxyglycolate, sodium glycocholate, sodium hydroxybenzoyal aminocaprylate, sodium lauryl sulfate, sodium taurocholate, stearic acid,thymol, tricaprylin, triolein, undecylenic acid, and a combinationthereof.

In some embodiments, the nasal spray formulation comprises: about 0.005%(w/v) to about 2.5% (w/v) dodecyl maltoside; about 0.001 (w/v) to about1% (w/v) benzalkonium chloride; about 0.001 (w/v) to about 1% (w/v)oleic acid, or salt thereof; a combination of about about 0.005% (w/v)to about 2.5% (w/v) dodecyl maltoside and about 0.001 (w/v) to about 1%(w/v) benzalkonium chloride; a combination of about about 0.005% (w/v)to about 2.5% (w/v) dodecyl maltoside and about 0.001 (w/v) to about 1%(w/v) oleic acid, or salt thereof; or a combination of about 0.001 (w/v)to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) to about1% (w/v) oleic acid, or salt thereof: or a combination of about 0.001(w/v) to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) toabout 1% (w/v) oleic acid, or salt thereof and 0.001% to 1% sodiummetabisulfite; or a combination of about 0.001 (w/v) to about 1% (w/v)benzalkonium chloride and about 0.001 (w/v) to about 1% (w/v) oleicacid, or salt thereof and about 0.001% to 10% polysorbate 80 and 0.001%to 1% sodium metabisulfite; or a combination of about 0.001 (w/v) toabout 1% (w/v) benzalkonium chloride and about 0.001 (w/v) to about 1%(w/v) oleic acid, or salt thereof and about 0.001% to 10% polysorbate 80and 0.001% to 1% sodium metabisulfite and 0.001% to 1% citric acid.

In some embodiments, the nasal spray formulation comprises: about 0.005%(w/v) to about 0.08% (w/v) benzalkonium chloride; about 0.01% (w/v) toabout 0.06% (w/v) benzalkonium chloride; or about 0.01% (w/v) to about0.04% (w/v) benzalkonium chloride; wherein the benzalkonium chloride isthe sole absorption enhancement agent in the nasal spray formulation oris in present in the formulation with one or more additional absorptionenhancement agents.

In some embodiments, the nasal spray formulation comprises: about 0.001%to 1% of any one of the antioxidants described herein, or a combinationof any one of the antioxidants described herein.

In some embodiments, the nasal spray formulation comprises a bufferingagent. Buffering agents include, but are not limited to, adipicacid,boric acid, calcium carbonate, calcium hydroxide, calcium lactate,calcium phosphate, tribasic, citric acid monohydrate, dibasic sodiumphosphate, diethanolamine, glycine, maleic acid, malic acid, methionine,monobasic sodium phosphate, monoethanolamine, monosodium glutamate,phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate,sodium borate, sodium carbonate, sodium citrate dihydrate, sodiumhydroxide, sodium lactate, and triethanolamine.

In one aspect, provided herein is a method of treatment of a conditionmediated by adrenergic receptors comprising the intranasaladministration of any one of the formulations as described herein. Insome embodiments, the condition is chosen from a type-1 hypersensitivityreaction (systemic allergic reaction), an acute asthmatic attack,cardiac arrest, and Stokes-Adams Syndrome. In some embodiments, thecondition is a type-1 hypersensitivity reaction (systemic allergicreaction). In some embodiments, the type 1 hypersensitivity reaction ischosen from allergic asthma, allergic conjunctivitis, allergic rhinitis,anaphylaxis, angioedema, urticaria, eosinophilia, drug allergy and foodallergy. In some embodiments, the drug allergy is an antibiotic allergy.

In one aspect, described herein is a nasal spray formulation comprisingepinephrine or a salt thereof, which when administered to a subjectyields one or more of the following pharmacokinetic features: both themean AUC_(0-20 min) and AUC_(0-t) are at least 80% of the AUC_(0-20 min)and AUC_(0-t) that a 0.3 mg intramuscular injection yields; a meanC_(max) that is at least 80% of the C_(max) and no more than 150% of theC_(max) that a 0.3 mg intramuscular injection yields; a mean t_(max) ofless than 45 minutes; or IM-injection like absorption under optimaldosing conditions in the thigh. In another aspect, described herein is anasal spray formulation comprising epinephrine or a salt thereof, whichwhen administered to a subject yields one or more of the followingpharmacokinetic features: both the mean AUC_(0-20 min) and AUC_(0-t) areat least 80% of the AUC_(0-20 min) and AUC_(0-t) that a 0.3 mgintramuscular injection yields; a mean C_(max) that is at least 80% ofthe C_(max) and no more than 150% of the C_(max) that a 0.3 mgintramuscular injection yields; a mean t_(max) of less than 45 minutes;and IM-injection like absorption under optimal dosing conditions in thethigh.

In another aspect, described herein is a nasal spray formulationcomprising epinephrine or a salt thereof, which when administered to asubject yields one or more of the following pharmacokinetic features:both the mean AUC_(0-20 min) and AUC_(0-t) are at least 80% of theAUC_(0-20 min) and AUC_(0-t) that a 0.15 mg intramuscular injectionyields; a mean C_(max) that is at least 80% of the C_(max) and no morethan 150% of the C_(max) that a 0.15 mg intramuscular injection yields;a mean t_(max) of less than 45 minutes; or IM-injection like absorptionunder optimal dosing conditions in the thigh. In another aspect,described herein is a nasal spray formulation comprising epinephrine ora salt thereof, which when administered to a subject yields one or moreof the following pharmacokinetic features: both the mean AUC_(0-20 min)and AUC_(0-t) are at least 80% of the AUC_(0-20 min) and AUC_(0-t) thata 0.15 mg intramuscular injection yields; a mean C_(max) that is atleast 80% of the C_(max) and no more than 150% of the C_(max) that a0.15 mg intramuscular injection yields; a mean t_(max) of less than 45minutes; and IM-injection like absorption under optimal dosingconditions in the thigh.

In yet another aspect, described herein is a nasal spray formulationcomprising epinephrine or a salt thereof, which when administered to asubject yields one or more of the following pharmacokinetic features:both the mean AUC_(0-20 min) and AUC_(0-t) are at least 80% of theAUC_(0-20 min) and AUC_(0-t) that a 0.5 mg intramuscular injectionyields; a mean C_(max) that is at least 80% of the C_(max) and no morethan 150% of the C_(max) that a 0.5 mg intramuscular injection yields; amean t_(max) of less than 45 minutes; or IM-injection like absorptionunder optimal dosing conditions in the thigh.

In some embodiments, the nasal spray formulation is a pharmaceuticalformulation.

In some embodiments, the epinephrine or salt thereof is present in thenasal spray formulation in an amount efficacious for the treatment of anacute hypersensitivity reaction.

In some embodiments, intranasal administration of a single dose of thenasal spray pharmaceutical formulation to a subject provides a plasmaepinephrine concentration that is efficacious for the treatment of anacute hypersensitivity reaction. In some embodiments, a single dose ofthe nasal spray pharmaceutical formulation comprises between about 0.5mg and about 2.0 mg of epinephrine, or a salt thereof. In someembodiments, a single dose of the nasal spray pharmaceutical formulationcomprises between about 0.5 mg and about 1.5 mg of epinephrine, or asalt thereof. In some embodiments, a single dose of the nasal spraypharmaceutical formulation comprises between about about 0.5 mg andabout 0.7 mg of epinephrine, or a salt thereof. In some embodiments, asingle dose of the nasal spray pharmaceutical formulation comprisesabout 1.0 mg of epinephrine, or a salt thereof. In some embodiments, asingle dose of the nasal spray pharmaceutical formulation comprisesbetween about 1.3 mg and about 1.5 mg of epinephrine, or a salt thereof.In some embodiments, the formulation is an aqueous solution, aqueoussuspension, aqueous emulsion, non-aqueous solution, non-aqueoussuspension, non-aqueous emulsion, pressurized metered-dose inhalers ordry powder.

In some embodiments, the nasal spray formulation is an aqueous solution,aqueous suspensions, aqueous emulsion, non-aqueous solution, non-aqueoussuspension or non-aqueous emulsion.

In some embodiments, the nasal spray formulation has intramuscular(IM)-injection-like pharmacokinetics when IM-injection is dosed in thelateral thigh, or subcutaneous (SC)-like absorption or in between.

In some embodiments, the nasal spray formulation has subcutaneous(SC)-like absorption and the SC pharmacokinetic profile has a C_(max) ofat least 100 pg/mL and AUC0-240 min of 150 h*pg/mL.

In some embodiments, the nasal spray formulation has intramuscular(IM)-injection-like absorption.

In some embodiments, the nasal spray formulation comprises an absorptionenhancer.

In some embodiments, the nasal spray pharmaceutical formulationcomprises one or more absorption enhancement agents; and optionally oneor more agents selected from isotonicity agents; stabilizing agents;preservatives; taste-masking agents; viscosity modifiers; antioxidants;buffers and pH adjustment agents; wherein the pH of the nasal spraypharmaceutical formulation is between about 2.0 and about 6.0. In someembodiments, the nasal spray pharmaceutical formulation has a pH betweenabout 3.0 and about 5.0. In some embodiments, the nasal spraypharmaceutical formulation has a pH of about 4.0.

In some embodiments, the nasal spray pharmaceutical formulationcomprises pH adjustment agents. In some embodiments, the pH adjustmentagent is an acid, a base, a buffer, or a combination thereof. In someembodiments, the acid is adipic acid, ammonium chloride, citric acid,acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionicacid, sulfuric acid or tartaric acid; the base is sodium hydroxide,sodium citrate, sodium bicarbonate, sodium carbonate; and the buffer isa phosphate buffer, acetate buffer, or citrate buffer.

In some embodiments, the nasal spray formulation comprises between about0.5 and about 1.1 molar equivalents of acid to each mole of epinephrine.In some embodiments, the acid is is adipic acid, ammonium chloride,citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoricacid, propionic acid, sulfuric acid or tartaric acid. In someembodiments, the acid is hydrochloric acid. In some embodiments, no baseis added to the formulation during its preparation. In some embodiments,the nasal spray formulation has a pH between about 2.0 and about 6.0. Insome embodiments, the nasal spray formulation has a pH of about 4.0.

In some embodiments, the nasal spray formulation comprises between about5 mg/mL and about 40 mg/mL per dose epinephrine, or a salt thereof. Insome embodiments, the nasal spray formulation comprises between about0.40 mg and about 2.40 mg per dose dispensed from the device ofepinephrine, or a salt thereof. In some embodiments, the nasal sprayformulation comprises between about 0.9 mg and about 2.40 mg per dosedispensed from the device of epinephrine, or a salt thereof. In someembodiments, the nasal spray formulation comprises between about 0.5 mgand about 2.0 mg per dose dispensed from the device of epinephrine, or asalt thereof. In some embodiments, the nasal spray formulation comprisesbetween about 0.9 mg and about 1.5 mg per dose dispensed from the deviceof epinephrine, or a salt thereof. In some embodiments, the nasal sprayformulation comprises between about 0.75 mg and about 1.5 mg per dosedispensed from the device of epinephrine, or a salt thereof. In someembodiments, the nasal spray formulation comprises between about 0.45 mgand about 1.15 mg per dose dispensed from the device of epinephrine, ora salt thereof. In some embodiments, the nasal spray formulationcomprises between about 1.0 mg and about 2.0 mg per dose dispensed fromthe device of epinephrine, or a salt thereof.

In some embodiments, the nasal spray formulation comprises one or moreabsorption enhancers selected from alcohol, aprotinin, benzalkoniumchloride, benzyl alcohol, capric acid, ceramides, cetylpyridiniumchloride, chitosan, cyclodextrins, deoxycholic acid, decanoyl, dimethylsulfoxide, glyceryl monooleate, glycofurol, glycofurol, glycosylatedsphingosines, glycyrrhetinic acids, 2-hydroxypropyl-β-cyclodextrin,laureth-9, lauric acid, lauroyl carnitine, lysophosphatidylcholine,menthol, poloxamer 407 or F68, poly-L-arginine, polyoxyethylene-9-laurylether, isopropyl myristate, isopropyl palmitate, lanolin, light mineraloil, linoleic acid, menthol, myristic acid, myristyl alcohol, oleicacid, oleyl alcohol, palmitic acid, polysorbate 20, polysorbate 80,propylene glycol, polyoxyethylene alkyl ethers, polyoxylglycerides,pyrrolidone, quillaia saponin, salicylic acid, sodium salt, β-sitosterolβ-D-glucoside, sodium lauryl sulfate, sucrose cocoate, taurocholic acid,taurodeoxycholic acid, taurodihydrofusidic acid, thymol, tricaprylin,triolein, and alkylsaccharides.

In some embodiments, the nasal spray formulation comprises one or moreabsorption enhancers selected from dodecyl maltoside, benzalkoniumchloride, oleic acid, or salt thereof, polysorbate 20, polysorbate 80,and sodium lauryl sulfate.

In some embodiments, the nasal spray formulation comprises: about 0.005%(w/v) to about 2.5% (w/v) dodecyl maltoside; about 0.001 (w/v) to about1% (w/v) benzalkonium chloride; about 0.001 (w/v) to about 1% (w/v)oleic acid, or salt thereof; a combination of about about 0.005% (w/v)to about 2.5% (w/v) dodecyl maltoside and about 0.001 (w/v) to about 1%(w/v) benzalkonium chloride; a combination of about about 0.005% (w/v)to about 2.5% (w/v) dodecyl maltoside and about 0.001 (w/v) to about 1%(w/v) oleic acid, or salt thereof, or a combination of about 0.001 (w/v)to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) to about1% (w/v) oleic acid, or salt thereof and about 0.001 to 1% of anantioxidant (e.g. sodium metabisulfite). In some embodiments, the nasalspray formulation comprises: about 0.005% (w/v) to about 2.5% (w/v)dodecyl maltoside; about 0.001 (w/v) to about 1% (w/v) benzalkoniumchloride; about 0.001 (w/v) to about 1% (w/v) oleic acid, or saltthereof, a combination of about about 0.005% (w/v) to about 2.5% (w/v)dodecyl maltoside and about 0.001 (w/v) to about 1% (w/v) benzalkoniumchloride; a combination of about about 0.005% (w/v) to about 2.5% (w/v)dodecyl maltoside and about 0.001 (w/v) to about 1% (w/v) oleic acid, orsalt thereof, or a combination of about 0.001 (w/v) to about 1% (w/v)benzalkonium chloride and about 0.001 (w/v) to about 1% (w/v) oleicacid, or salt thereof. In some embodiments, the nasal spray formulationcomprises: about 0.005% (w/v) to about 0.08% (w/v) benzalkoniumchloride; about 0.01% (w/v) to about 0.06% (w/v) benzalkonium chloride;or about 0.01% (w/v) to about 0.04% (w/v) benzalkonium chloride; whereinthe benzalkonium chloride is the sole absorption enhancement agent inthe nasal spray formulation or is in present in the formulation with oneor more additional absorption enhancement agents.

In some embodiments, the nasal spray formulation additionally comprisesa stabilizing agent. In some embodiments, the stabilizing agent isethylenediaminetetraacetic acid (EDTA) or a salt thereof. In someembodiments, the EDTA is disodium EDTA. In some embodiments, the EDTA ispresent in an amount that is from about 0.001% to about 1%.

In some embodiments, the nasal spray formulation additionally comprisesa preservative. In some embodiments, the preservative is benzalkoniumchloride.

In one aspect, described herein is a method of treatment of a conditionmediated by adrenergic receptors comprising the intranasaladministration of any one of the formulation described herein. In someembodiments, the condition is chosen from a type-1 hypersensitivityreaction (systemic allergic reaction), an acute asthmatic attack,cardiac arrest, and Stokes-Adams Syndrome. In some embodiments, thecondition is a type-1 hypersensitivity reaction (systemic allergicreaction). In some embodiments, the type 1 hypersensitivity reaction ischosen from allergic asthma, allergic conjunctivitis, allergic rhinitis,anaphylaxis, angioedema, urticaria, eosinophilia, drug allergy and foodallergy. In some embodiments, the drug allergy is an antibiotic allergy.

In another aspect, described herein is a method of treatment ofanaphylaxis comprising the intranasal administration of an intranasalformulation of epinephrine in an amount less than about 2.0 mg. In someembodiments, the nasal pharmaceutical formulation comprises betweenabout 0.5 mg and about 1.5 mg of epinephrine, or a salt thereof. In someembodiments, the nasal pharmaceutical formulation comprises betweenabout about 0.5 mg and about 0.7 mg of epinephrine, or a salt thereof.In some embodiments, the nasal pharmaceutical formulation comprisesabout 1.0 mg of epinephrine, or a salt thereof. In some embodiments, thenasal pharmaceutical formulation comprises between about 1.3 mg andabout 1.5 mg of epinephrine, or a salt thereof.

In some embodiments of the methods of treatments, the intranasalformulation comprises: one or more absorption enhancement agents; anisotonicity agent; a stabilizing agent; a preservative; an optionalantioxidant; and optional pH adjustment agents. In some embodiments ofthe methods of treatment, the one or more absorption enhancement agentsare selected from: dodecyl maltoside; benzalkonium chloride; oleic acid,or salt thereof; sodium laural sulfate; a combination of dodecylmaltoside and benzalkonium chloride; a combination of dodecyl maltosideand oleic acid, or salt thereof; and a combination of benzalkoniumchloride and oleic acid, or salt thereof. In some embodiments of themethods of treatment, the one or more absorption enhancement agents areselected from: about 0.005% (w/v) to about 2.5% (w/v) dodecyl maltoside;about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride; about 0.001(w/v) to about 1% (w/v) oleic acid, or salt thereof; a combination ofabout about 0.005% (w/v) to about 2.5% (w/v) dodecyl maltoside and about0.001 (w/v) to about 1% (w/v) benzalkonium chloride; a combination ofabout about 0.005% (w/v) to about 2.5% (w/v) dodecyl maltoside and about0.001 (w/v) to about 1% (w/v) oleic acid, or salt thereof; or acombination of about 0.001 (w/v) to about 1% (w/v) benzalkonium chlorideand about 0.001 (w/v) to about 1% (w/v) oleic acid, or salt thereof. Insome embodiments of the methods of treatment, the formulation comprises:about 0.005% (w/v) to about 0.08% (w/v) benzalkonium chloride; about0.01% (w/v) to about 0.06% (w/v) benzalkonium chloride; or about 0.01%(w/v) to about 0.04% (w/v) benzalkonium chloride; wherein thebenzalkonium chloride is the sole absorption enhancement agent in theformulation or is in present in the formulation with one or moreabsorption enhancement agents. In some embodiments of the methods oftreatment, the isotonicity agent is sodium chloride. In some embodimentsof the methods of treatment, the stabilizing agent is EDTA. In someembodiments of the methods of treatment, the stabilizing agent is EDTAin an amount from about 0.001% (w/v) to about 1% (w/v). In someembodiments of the methods of treatment, the preservative isbenzalkonium chloride. In some embodiments of the methods of treatment,the preservative is benzalkonium chloride in an amount from about 0.001%(w/v) to about 1% (w/v).

Articles of manufacture, which include packaging material, a nasal sprayformulation described herein within the packaging material, and a labelthat indicates that the nasal spray formulation is used for thetreatment of any of the conditions described herein (e.g. anaphylaxis)are provided.

Other objects, features and advantages of the compositions and methodsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only, since variouschanges and modifications within the spirit and scope of the instantdisclosure will become apparent to those skilled in the art from thisdetailed description.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows the area under the plasma concentration versus time curveat time 0-120 minutes (AUC_(0-120 min)) of epinephrine absorption atdifferent dosages and routes of administration as disclosed in Srisawatet al., “A preliminary study of intranasal epinephrine administration asa potential route for anaphylaxis treatment,” Asian Pac J AllergyImmunol, 2016 March; 34(1):38-43, discussed below.

FIG. 2 shows the plasma epinephrine concentration versus time plotsafter administrations of IN saline, IN epinephrine at 5 mg, and IMepinephrine at 0.3 mg, as disclosed in Srisawat et al.

FIG. 3 shows the mean plasma epinephrine concentrations above baseline(pg/mL) vs. time (min) curves from the first clinical study described inExample 2A comparing 0.3 mg epinephrine IM and IN; the curve withsquared represents IM, and the curve with circles, IN.

FIG. 4 shows the mean plasma epinephrine concentrations above baseline(pg/mL) vs. time (min) curves from the second clinical study describedin Example 2B comparing 0.5, 1.0, and 2.0 mg epinephrine IN. The curvewith circles represents 0.5 mg; the curve with triangles, 1.0 mg, andthe curve with squares, 2.0 mg.

FIG. 5 shows the first 30 minutes of the mean plasma epinephrineconcentrations above baseline (pg/mL) vs. time (min) curves from thesecond clinical study described in Example 2B comparing 0.5, 1.0, and2.0 mg IN epinephrine. The curve with circles represents 0.5 mg; thecurve with triangles, 1.0 mg, and the curve with squares, 2.0 mg.

FIG. 6 repeats the data from FIG. 4 and overlays it with the mean plasmaconcentration vs. time curve for IM epinephrine from the first clinicalstudy described in Example 2A.

FIG. 7 repeats the data from FIG. 5 and overlays it with the first 30minutes of the mean plasma concentration vs. time curve for IMepinephrine from the first clinical study described in Example 2A.

FIG. 8 shows the mean plasma epinephrine concentrations above baseline(pg/mL) vs. time (min) curves from the comparative bioavailabilityportion of the second clinical study described in Example 2B, comparing1.0 mg epinephrine IN (curve w/ circles) to 0.3 mg epinephrine IM(epinephrine auto injector, curve w/ triangles).

FIG. 9 shows the first 30 minutes of the mean plasma epinephrineconcentrations above baseline (pg/mL) vs. time (min) curves from thecomparative bioavailability portion of the second clinical studydescribed in Example 2B, comparing 1.0 mg epinephrine IN (curvew/circles) to 0.3 mg epinephrine IM (EpiPen®, curve w/ triangles).

DETAILED DESCRIPTION

Disclosed herein are methods and formulations useful for the treatmentof anaphylaxis and other conditions, comprising administering anintranasal formulation of epinephrine. Also provided are devices adaptedfor nasal delivery of a pharmaceutical formulation to a patient,including single, bi- and multidose delivery comprising atherapeutically effective amount of epinephrine and pharmaceuticallyacceptable salts thereof.

Intranasal epinephrine has a long history of use in low doses as adecongestant and as a vasoconstrictor, often formulated combination withanaesthetic, in sinus and nasal surgery. Historically, epinephrine hasbeen difficult to formulate as an intranasal solution for systemicdelivery. See, e.g., Srisawat C et al., “A preliminary study ofintranasal epinephrine administration as a potential route foranaphylaxis treatment,” Asian Pac J Allergy Immunol, 2016 March;34(1):38-43. Srisawat showed that significant systemic absorption ofepinephrine via the IN route was observed only at 5 mg (see FIG. 1 ) andthe pharmacokinetic parameters of IN epinephrine even at 5 mg were alsonot significantly different from those of the IM epinephrine group (seeTable 1, below).

TABLE 1 Intramuscular and Intranasal Administraton of Epinephrine (fromSrisawat (2016). Intramuscular (IM) Intranasal (IN) Mean ± SDEpinephrine 0.3 mg Epinephrine 5 mg C_(baseline) (pg/mL)  35 ± 23 8 ± 6C_(max) (pg/mL) 309 ± 88 386 ± 152 T_(max) (min)  67 ± 43 70 ± 17AUC_(0-120 min) 18.3 ± 9.3 19.4 ± 12.1 (ng*min/mL)

FIG. 1 is reproduced from Srisawat C et al. and demonstrates thatSrisawat et al. observed no blood level of epinephrine at the intranasaldose level of 2.5 mg and below.

Furthermore, FIG. 2 shows that even at a dose of 5 mg, Srisawat was notable to make an intranasal formulation that could achieve a higherplasma concentration than intramuscular epinephrine delivered by autoinjector at any time point before about 60 minutes, thus absorptionduring the critical early time points was delayed when rapid absorptionis needed to stop the systemic allergic reaction (anaphylaxis). This ispotentially detrimental in serious conditions such as anaphylaxis whereimmediate treatment, and thus injection-like pharmacokinetics, aredesirable. The PK profile of IM injection into the thigh is consideredthe optimal dosing method by literature given that the highervascularity of the leg muscle allows for more rapid absorption anddistribution of the epinephrine providing a rapid increase in plasmalevels to stop the anaphylaxis reaction much sooner than other routes ofadministration. FIG. 2 also shows that Srisawat's 5 mg formulation, incontrast to intramuscular epinephrine delivered by auto injector,cleared from the plasma almost entirely in about two hours. Finally,epinephrine is known to be associated with dose-related cardiac sideeffects including myocardial infarction, at doses as low as 0.3 to 0.5mg intramuscularly; accordingly, doses as high as 5 mg would likely berisky in the general population if nasal conditions existed that mayallow excessive absorption. Thus, lower dose preparations that wouldavoid such risks are preferred as a safer nasal preparation.

Disclosed herein are intranasal formulations of epinephrine, and nasalspray devices comprising the formulations, that solve the problems ofpast attempts. Various aspects may contribute to the success of theformulations, devices, and methods of use disclosed herein.

For example, in certain embodiments, formulating epinephrine in anaqueous solution with the appropriate addition of molar equivalents ofacid to each mole of said epinephrine helps to solubilize and stabilizethe epinephrine. This allows the formulation to avoid the use ofbuffering agents commonly used in aqueous pharmaceutical compositionsfor injection, including phosphate, acetate, and citrate buffers, whichare sometimes avoided in the nasal formulations disclosed herein. Othersalts of epinephreine, such as epinephrine acetate, epinephrinehydrochloride, epinephrine tartrate, epinephrine bitartrate, epinephrinehydrogen tartrate and epinephrine borate can also be used to formulateaqueous solutions of epinephrine.

Certain embodiments of the formulations, devices, and methods of usedisclosed herein offer advantages over epinephrine formulated in otherways. Epinephrine is considered a narrow therapeutic index drug. As asympathomimetic catecholamine, epinephrine has a narrow therapeuticindex and serious adverse reactions including cardiovascular andcerebrovascular reactions can be associated with its use. Nevertheless,the use epinephrine for this indication is life saving and the benefitsof using it outweigh the potential safety risks. Intranasal delivery andformulation are suited for the safe, painless delivery of drugs such asepinephrine by consistent content uniformity, delivery amount andabsorption, thereby minimizing serious adverse reactions includingcardiovascular and cerebrovascular reactions that can be associated withits use via injection mechanisms. Shot weights have low variability andconsistently deliver the labeled dose.

In one aspect, described herein is a pharmaceutical compositioncomprising: a) epinephrine; and b) an alkylglycoside; wherein thepharmaceutical composition is formulated for administration into thecirculatory system of a subject via the intranasal, inhalation, orpulmonary, administration route. In some embodiments, described hereinis a pharmaceutical composition comprising: a) epinephrine; and b) analkylglycoside; wherein the pharmaceutical composition is a liquidformulated for intranasal delivery.

In some embodiments, the alkylglycoside has an alkyl chain includingbetween 8 to 20 carbons. In some embodiments, the alkylglycoside isselected from the group consisting of undecyl maltoside, dodecylmaltoside, tridecyl maltoside, tetradecyl maltoside, sucrosemono-dodecanoate, sucrose mono-tridecanoate, and sucrosemono-tetradecanoate. In some embodiments, the alkylglycoside isdodecyl-beta-D-maltoside. In some embodiments, the alkylglycosideconcentration is between about 0.001% and 10.0% (w/v). In someembodiments, the alkylglycoside concentration is between about 0.05% and0.5% (w/v).

In some embodiments, the composition further comprises a membranepenetration-enhancing agent. In some embodiments, the membranepenetration-enhancing agent is a surfactant, a bile salt, aphospholipid, an alcohol, an enamine, a long-chain amphipathic molecule,a small hydrophobic molecule, sodium or a salicylic acid derivative, aglycerol ester of acetoacetic acid, a cyclodextrin, a medium-chain orlong chain fatty acids, a chelating agent, an amino acid or saltthereof, an enzyme or combination thereof. In some embodiments, themembrane penetration-enhancing agent is selected from the groupconsisting of citric acid, sodium citrate, propylene glycol, glycerin,ascorbic acid, sodium metabisulfite, ethylenediaminetetraacetic acid(EDTA) disodium, benzalkonium chloride, hydroxyquinolone, sodiumhydroxide, and combinations thereof. In some embodiments, the membranepenetration-enhancing agent is selected from the group consisting ofcitric acid, sodium citrate, propylene glycol, glycerin, ascorbic acid,sodium metabisulfite, ethylenediaminetetraacetic acid (EDTA) disodium,benzalkonium chloride, sodium hydroxide, and combinations thereof. Insome embodiments, membrane penetration-enhancing agent is benzalkoniumchloride, EDTA, or a combination thereof.

In some embodiments, the composition provides a Cmax for the epinephrinein a subject that is about 2 fold or greater as compared toadministration without alkylglycoside.

In some embodiments, the composition provides a Tmax for the epinephrinein a subject that is about 2 fold or less as compared to administrationwithout alkylglycoside.

In some embodiments, the composition provides a Tmax for the epinephrineof about 0.3 hours or less in a subject.

In some embodiments, the composition has a pH of about 2.0 to 6.0. Insome embodiments, the composition has a pH of about 2.0 to 5.0.

In another aspect, described herein is a method of increasing thebioavailability of epinephrine in a subject comprising administering toa subject a pharmaceutical composition comprising epinephrine and analkylglycoside, thereby increasing the bioavailability of theepinephrine in the subject; wherein the pharmaceutical composition isformulated for administration into the circulatory system of a subjectvia the intranasal, inhalation, or pulmonary, administration route. Insome embodiments, described herein is a method of increasing thebioavailability of epinephrine in a subject comprising administering toa subject a pharmaceutical composition comprising epinephrine and analkylglycoside, thereby increasing the bioavailability of theepinephrine in the subject; wherein the pharmaceutical composition is aliquid formulated for intranasal delivery.

In some embodiments, increasing the bioavailabilty of epinephrinepermits for lower dose amounts of epeinpehrine to be deliveredintrasally and be efficacious for treating anaphylaxis. In someembodiments, exposure to larger doses of epinephrine can result in anepinephrine overdose. There is increased interest and need in developingalternative non-invasive epinephrine dosage forms that provideepinephrine plasma concentrations equivalent to those obtained byepinephrine auto-injectors, available in a range of doses, have a longshelf-life, and be free from needle anxiety, the possibility ofadministration error, unintentional injection and injury. Epinephrinenasal dosage forms described herein offer the potential of beinguser-friendly, non-invasive alternatives for the first-aid emergencytreatment of anaphylaxis in community settings.

In some embodiments, the alkylglycoside has an alkyl chain includingbetween 8 to 20 carbons. In some embodiments, the alkylglycoside isselected from the group consisting of undecyl maltoside, dodecylmaltoside, tridecyl maltoside, tetradecyl maltoside, sucrosemono-dodecanoate, sucrose mono-tridecanoate, and sucrosemono-tetradecanoate. In some embodiments, the alkylglycoside isdodecyl-beta-D-maltoside. In some embodiments, the alkylglycosideconcentration is between about 0.001% and 10.0% (w/v). In someembodiments, the alkylglycoside concentration is between about 0.05% and0.5% (w/v).

In some embodiments, the composition further comprises a membranepenetration-enhancing agent. In some embodiments, the membranepenetration-enhancing agent is a surfactant, a bile salt, aphospholipid, an alcohol, an enamine, a medium and/or long-chainamphipathic molecules, a small hydrophobic molecule, sodium or asalicylic acid derivative, a glycerol ester of acetoacetic acid, acyclodextrin, a medium-chain or long chain fatty acids, a chelatingagent, an amino acid or salt thereof, an enzyme or combination thereof.In some embodiments, the membrane penetration-enhancing agent isselected from the group consisting of citric acid, sodium citrate,propylene glycol, glycerin, ascorbic acid, sodium metabisulfite,ethylenediaminetetraacetic acid (EDTA) disodium, benzalkonium chloride,sodium hydroxide, and combinations thereof. In some embodiments, themembrane penetration-enhancing agent is benzalkonium chloride, EDTA, ora combination thereof.

In some embodiments, the composition provides a Cmax for the epinephrinein the subject that is about 2 fold or greater as compared toadministration without alkylglycoside.

In some embodiments, the composition provides a Tmax for the epinephrinein the subject that is about 2 fold or less as compared toadministration without alkylglycoside.

In some embodiments, the composition provides a Tmax for the epinephrineof about 0.3 hours or less in the subject.

In some embodiments, the composition has a pH of about 2.0 to 6.0. Insome embodiments, the composition has a pH of about 2.0 to 5.0.

In some embodiments, compositions described here are liquid compositionssuitable for intranasal administration.

In one aspect, the invention provides a method of increasing absorptionof epinephrine into the circulatory system of a subject byadministering, via the nasal, inhalation or pulmonary delivery route acomposition comprising: (a) epinephrine; (b) an absorption increasingamount of a suitable nontoxic, nonionic alkylglycoside having ahydrophobic alkyl group joined by a linkage to a hydrophilic saccharide;and (c) a mucosal delivery-enhancing agent.

The term, “mucosal delivery-enhancing agent” includes agents whichenhance the release or solubility (e.g., from a formulation deliveryvehicle), diffusion rate, penetration capacity and timing, uptake,residence time, stability, effective half-life, peak or sustainedconcentration levels, clearance and other desired mucosal deliverycharacteristics (e.g., as measured at the site of delivery, or at aselected target site of activity such as the bloodstream or centralnervous system) of a compound(s) (e.g., biologically active compound).Enhancement of mucosal delivery can occur by any of a variety ofmechanisms, including, for example, by increasing the diffusion,transport, persistence or stability of the compound, increasing membranefluidity, modulating the availability or action of calcium and otherions that regulate intracellular or paracellular permeation,solubilizing mucosal membrane components (e.g., lipids), changingnon-protein and protein sulfhydryl levels in mucosal tissues, increasingwater flux across the mucosal surface, modulating epithelial junctionphysiology, reducing the viscosity of mucus overlying the mucosalepithelium, reducing mucociliary clearance rates, and other mechanisms.

Exemplary mucosal delivery enhancing agents include the following agentsand any combinations thereof:

-   -   (a) an aggregation inhibitory agent;    -   (b) a charge-modifying agent;    -   (c) a pH control agent;    -   (d) a degradative enzyme inhibitory agent;    -   (e) a mucolytic or mucus clearing agent;    -   (f) a ciliostatic agent;    -   (g) a membrane penetration-enhancing agent selected from:        -   (i) a surfactant;        -   (ii) a bile salt;        -   (ii) a phospholipid additive, mixed micelle, liposome, or            carrier;        -   (iii) an alcohol;        -   (iv) an enamine;        -   (v) an NO donor compound;        -   (vi) a long-chain amphipathic molecule;        -   (vii) a small hydrophobic penetration enhancer;        -   (viii) sodium or a salicylic acid derivative;        -   (ix) a glycerol ester of acetoacetic acid;        -   (x) a cyclodextrin or beta-cyclodextrin derivative;        -   (xi) a medium-chain fatty acid;        -   (xii) a chelating agent;        -   (xiii) an amino acid or salt thereof;        -   (xiv) an N-acetylamino acid or salt thereof;        -   (xv) an enzyme degradative to a selected membrane component;        -   (ix) an inhibitor of fatty acid synthesis;        -   (x) an inhibitor of cholesterol synthesis; and        -   (xi) any combination of the membrane penetration enhancing            agents recited in (i)-(x);    -   (h) a modulatory agent of epithelial junction physiology;    -   (i) a vasodilator agent;    -   (j) a selective transport-enhancing agent; and    -   (k) a stabilizing delivery vehicle, carrier, mucoadhesive,        support or complex-forming species with which the compound is        effectively combined, associated, contained, encapsulated or        bound resulting in stabilization of the compound for enhanced        nasal mucosal delivery, wherein the formulation of the compound        with the intranasal delivery-enhancing agents provides for        increased bioavailability of the compound in a blood plasma of a        subject.

Additional mucosal delivery-enhancing agents include, for example,citric acid, sodium citrate, propylene glycol, glycerin, ascorbic acid(e.g., L-ascorbic acid), sodium metabisulfite,ethylenediaminetetraacetic acid (EDTA) disodium, benzalkonium chloride,sodium hydroxide, and mixtures thereof. For example, EDTA or its salts(e.g., sodium or potassium) are employed in amounts ranging from about0.01% to 2% by weight of the composition containing alkylsaccharidepreservative.

In yet another aspect, described herein is a pharmaceutical compositionhaving a suitable nontoxic, nonionic alkylglycoside having a hydrophobicalkyl group joined by a linkage to a hydrophilic saccharide incombination with a mucosal delivery-enhancing agent selected from:

-   -   (a) an aggregation inhibitory agent;    -   (b) a charge-modifying agent;    -   (c) a pH control agent;    -   (d) a degradative enzyme inhibitory agent;    -   (e) a mucolytic or mucus clearing agent;    -   (f) a ciliostatic agent;    -   (g) a membrane penetration-enhancing agent selected from:        -   (i) a surfactant;        -   (ii) a bile salt;        -   (ii) a phospholipid additive, mixed micelle, liposome, or            carrier;        -   (iii) an alcohol;        -   (iv) an enamine;        -   (v) an NO donor compound;        -   (vi) a long-chain amphipathic molecule;        -   (vii) a small hydrophobic penetration enhancer;        -   (viii) sodium or a salicylic acid derivative;        -   (ix) a glycerol ester of acetoacetic acid;        -   (x) a cyclodextrin or beta-cyclodextrin derivative;        -   (xi) a medium-chain or long chain fatty acid;        -   (xii) a chelating agent;        -   (xiii) an amino acid or salt thereof;        -   (xiv) an N-acetylamino acid or salt thereof;        -   (xv) an enzyme degradative to a selected membrane component;        -   (ix) an inhibitor of fatty acid synthesis;        -   (x) an inhibitor of cholesterol synthesis; and        -   (xi) any combination of the membrane penetration enhancing            agents recited in (i)-(x);    -   (h) a modulatory agent of epithelial junction physiology;    -   (i) a vasodilator agent;    -   (j) a selective transport-enhancing agent; and    -   (k) a stabilizing delivery vehicle, carrier, mucoadhesive,        support or complex-forming species with which the compound is        effectively combined, associated, contained, encapsulated or        bound resulting in stabilization of the compound for enhanced        nasal mucosal delivery, wherein the formulation of the compound        with the intranasal delivery-enhancing agents provides for        increased bioavailability of the compound in a blood plasma of a        subject.

In another embodiment, described herein is a method of administering analkylglycoside composition by administering a therapeutically effectiveamount of at least one alkyglycoside having an alkyl chain length fromabout 12 to about 14 carbon atoms, at least one saccharide with anantibacterial activity, and epinephrine.

In one aspect, provided herein is an antibacterial alkylsaccharidecomposition, which includesn-dodecyl-4-O-α-D-glucopyranosyl-β-D-glucopyranoside orn-tetradecyl-4-O-α-D-glucopyranosyl-β-D-glucopyranoside.

Accordingly, provided herein is Embodiment 1, a nasal spray formulationcomprising between about 0.40 mg and about 2.40 mg per dose dispensedfrom the device of epinephrine, or a salt thereof. AlternativeEmbodiment 1, a nasal spray formulation comprising between about 0.40 mgand about 2.0 mg per dose dispensed from the device of epinephrine, or asalt thereof.

Embodiment 2. The nasal spray formulation as recited in Embodiment 1,wherein the formulation is a pharmaceutical formulation.

Embodiment 3. The nasal spray formulation as recited in Embodiment 2,wherein the epinephrine or salt thereof is present in the pharmaceuticalformulation in an amount efficacious for the treatment of an acutehypersensitivity reaction.

Embodiment 4. The nasal spray formulation as recited in any ofEmbodiments 1-3, wherein the formulation is aqueous.

Embodiment 5 The nasal spray formulation as recited in any ofEmbodiments 1-4, wherein the formulation comprises an absorptionenhancer. In alternative Embodiment 5, the nasal spray formulation asrecited in any of Embodiments 1-4, wherein the formulation comprises oneor more absorption enhancers.

Embodiment 6. The nasal spray formulation as recited in any ofEmbodiments 1-5, wherein the formulation has intramuscular(IM)-injection-like or subcutaneous (SQ)-like absorption, or in between.

Embodiment 7. The nasal spray formulation as recited in Embodiment 6,wherein has intramuscular (IM)-injection-like absorption.

Embodiment 8. The nasal spray formulation as recited in Embodiment 6,wherein the formulation has subcutaneous (SC)-like absorption.

Embodiment 9. The nasal spray formulation as recited in Embodiment 8where the SC pharmacokinetic profile has a C_(max) of at least 100 pg/mLand AUC_(0-240 min) of 150 h*pg/mL.

Embodiment 10. The nasal spray formulation as recited in any ofEmbodiments 1-9, wherein the formulation, when administered to asubject, yields one or more of the following pharmacokinetic features:

-   -   both the mean AUC_(0-20 min) and AUC_(0-t) are at least 80% of        the AUC_(0-20 min) and AUC_(0-t) that a 0.3 mg intramuscular        injection yields;    -   a mean C_(max) that is at least 80% of the C_(max) and no more        than 150% of the C_(max) that a 0.3 mg intramuscular injection        yields;    -   a mean t_(max) of less than 45 minutes; and    -   IM-injection like absorption under optimal dosing conditions in        the thigh.

Embodiment 11. The nasal spray formulation as recited in any ofEmbodiments 1-9, wherein the formulation, when administered to asubject, yields one or more of the following pharmacokinetic features:

-   -   both the mean AUC_(0-20 min) and AUC_(0-t) are at least 80% of        the AUC_(0-20 min) and AUC_(0-t) that a 0.15 mg intramuscular        injection yields;    -   a mean C_(max) that is at least 80% of the C_(max) and no more        than 150% of the C_(max) that a 0.15 mg intramuscular injection        yields;    -   a mean t_(max) of less than 45 minutes; and    -   IM-injection like absorption under optimal dosing conditions in        the thigh.

Embodiment 12. The nasal spray formulation as recited in any ofEmbodiments 1-9, wherein the formulation, when administered to asubject, yields one or more of the following pharmacokinetic features:

-   -   both the mean AUC_(0-20 min) and AUC_(0-t) are at least 80% of        the AUC_(0-20 min) and AUC_(0-t) that a 0.5 mg intramuscular        injection yields;    -   a mean C_(max) that is at least 80% of the C_(max) and no more        than 150% of the C_(max) that a 0.5 mg intramuscular injection        yields;    -   a mean t_(max) of less than 45 minutes; and    -   IM-injection like absorption under optimal dosing conditions in        the thigh.

Embodiment 13. The nasal spray formulation as recited in Embodiment1-12, wherein the formulation, when administered to a subject, yields at_(max) of less than 40 minutes, a t_(max) of less than 35 minutes, at_(max) of between 30 and 45 minutes, a t_(max) of between 30 and 40minutes, or a t_(max) of between 30 and 35 minutes. AlternativeEmbodiment 13. The nasal spray formulation as recited in Embodiment1-12, wherein the formulation, when administered to a subject, yields at_(max) of less than 40 minutes, a t_(max) of less than 35 minutes, at_(max) of between 15 and 45 minutes, a t_(max) of between 20 and 45minutes, a t_(max) of between 25 and 45 minutes, a t_(max) of between 30and 45 minutes, a t_(max) of between 30 and 40 minutes, a t_(max) ofbetween 30 and 35 minutes, a t_(max) of between 15 and 20 minutes, at_(max) of between 15 and 25 minutes, or a t_(max) of between 15 and 30minutes.

Embodiment 14. The nasal spray formulation as recited in any ofEmbodiments 1-13, wherein the formulation comprises less than one molarequivalents of acid to each mole of epinephrine.

Embodiment 15. The nasal spray formulation as recited in any ofEmbodiments 1-13, wherein the formulation comprises between about 0.5and about 1.1 molar equivalents of acid to each mole of epinephrine.

Embodiment 16. The nasal spray formulation as recited in either ofEmbodiments 14 and 15, wherein the acid is hydrochloric acid.Alternative Embodiment 16, The nasal spray formulation as recited ineither of Embodiments 14 and 15, wherein the acid is acetic acid, adipicacid, ammonium chloride, boric acid, citric acid, hydrochloric acid,lactic acid, phosphoric acid, propionic acid, sulfuric acid, or tartaricacid.

Embodiment 17. The nasal spray formulation as recited in any ofEmbodiments 1-16, wherein the formulation has a pH between about 3.0 andabout 6.0. Alternative Embodiment 17. The nasal spray formulation asrecited in any of Embodiments 1-16, wherein the formulation has a pHbetween about 2.0 and about 6.0.

Embodiment 18. The nasal spray formulation as recited in Embodiment 17,wherein the formulation has a pH between about 3.5 and about 5.0.

Embodiment 19. The nasal spray formulation as recited in Embodiment 17,wherein the formulation has a pH between about 4.0 and about 4.5.

Embodiment 20. The nasal spray formulation as recited in Embodiment 17,wherein the formulation has a pH of about 4.5.

Embodiment 21. The nasal spray formulation as recited in Embodiment 17,wherein the formulation has a pH of about 4.0.

Embodiment 22. The nasal spray formulation as recited in any ofEmbodiments 1-21, wherein the formulation comprises between about 5mg/mL and about 40 mg/mL epinephrine, or a salt thereof. AlternativeEmbodiment 22. The nasal spray formulation as recited in any ofEmbodiments 1-21, wherein the formulation comprises between about 3mg/mL and about 40 mg/mL epinephrine, or a salt thereof.

Embodiment 23. The nasal spray formulation as recited in any ofEmbodiments 1-22, wherein the formulation comprises between about 0.9 mgand about 2.4 mg per dose dispensed from the device of epinephrine, or asalt thereof.

Embodiment 24. The nasal spray formulation as recited in any ofEmbodiments 1-22, wherein the formulation comprises between about 0.5 mgand about 2.0 mg per dose dispensed from the device of epinephrine, or asalt thereof.

Embodiment 25. The nasal spray formulation as recited in any ofEmbodiments 1-22, wherein, the formulation comprises between about 0.75mg and about 1.5 mg per dose dispensed from the device of epinephrine,or a salt thereof.

Embodiment 26. The nasal spray formulation as recited in any ofEmbodiments 1-22, wherein the formulation comprises between about 0.9 mgand about 1.15 mg per dose dispensed from the device of epinephrine, ora salt thereof.

Embodiment 27. The nasal spray formulation as recited in any ofEmbodiments 1-22, wherein the formulation comprises about 1.0 mg perdose dispensed from the device of epinephrine, or a salt thereof.

Embodiment 28. The nasal spray formulation as recited in any ofEmbodiments 1-22, wherein the formulation comprises between about 0.45mg and about 1.15 mg per dose dispensed from the device of epinephrine,or a salt thereof.

Embodiment 29. The nasal spray formulation as recited in any ofEmbodiments 1-22, wherein the formulation comprises between about 1.0 mgand about 2.0 mg per dose dispensed from the device of epinephrine, or asalt thereof.

Embodiment 30. The nasal spray formulation as recited in any ofEmbodiments 1-29, wherein the formulation additionally comprises astabilizing agent.

Embodiment 31. The nasal spray formulation as recited in Embodiment 30,wherein the stabilizing agent is ethylenediaminetetraacetic acid (EDTA)or a salt thereof.

Embodiment 32. The nasal spray formulation as recited in Embodiment 31,wherein the EDTA is disodium EDTA.

Embodiment 33. The nasal spray formulation as recited in Embodiment 31or 32, wherein the EDTA is present in an amount that is from 5% to 15%of the amount of the epinephrine, both measured in mmol. AlternativeEmbodiment 33. The nasal spray formulation as recited in Embodiment 31or 32, wherein the EDTA is present in an amount that is from 0.001%(w/v) to 1% (w/v).

Embodiment 34. The nasal spray formulation as recited in Embodiment 31or 32, wherein the mmol of EDTA is about 10% of the mmol of theepinephrine.

Embodiment 35. The nasal spray formulation as recited in any ofEmbodiments 1-34, wherein the formulation additionally comprises apreservative.

Embodiment 36. The nasal spray formulation as recited in Embodiment 35,wherein the preservative is benzalkonium chloride.

Embodiment 37. The nasal spray formulation as recited in any ofEmbodiments 1-34, wherein the formulation additionally comprises anabsorption enhancer.

Embodiment 38. The nasal spray formulation as recited in Embodiment 37,wherein the absorption enhancer is an alkylsaccharide.

Embodiment 39. The nasal spray formulation as recited in Embodiment 38,wherein the absorption enhancer is dodecyl maltoside.

Embodiment 40. The nasal spray formulation as recited in Embodiment 39,wherein the formulation comprises about 0.005% (w/v) to about 2.5% (w/v)dodecyl maltoside.

Embodiment 41. The nasal spray formulation as recited in Embodiment 40,wherein the formulation comprises about 0.1% (w/v) to about 0.5% (w/v)dodecyl maltoside.

Embodiment 42. The nasal spray formulation as recited in Embodiment 41,wherein the formulation comprises about 0.25% (w/v) dodecyl maltoside.Alternative Embodiment 42. The nasal spray formulation as recited inEmbodiment 41, wherein the formulation comprises about 0.25% (w/v)dodecyl maltoside and about 0.001 (w/v) to about 1% (w/v) benzalkoniumchloride. Alternative Embodiment 42. The nasal spray formulation asrecited in Embodiment 41, wherein the formulation comprises about 0.25%(w/v) dodecyl maltoside and about 0.001 (w/v) to about 1% (w/v) Oleicacid, or salt thereof. Alternative Embodiment 42. The nasal sprayformulation as recited in Embodiment 41, wherein the formulationcomprises about 0.25% (w/v) dodecyl maltoside, about 0.001 to about 1%(w/v) benzalkonium chloride and about 0.001 to about 1% (w/v) oleicacid, or salt thereof.

Embodiment 43a. In certain embodiments, the formulation comprisesbetween about 0.75 mg and about 1.5 mg per dose dispensed from thedevice of epinephrine, or a salt thereof, and when administered as anasal spray to a subject yields one or more of the followingpharmacokinetic features:

-   -   both the mean AUC_(0-20 min) and AUC_(0-t) are at least 80% of        the AUC_(0-20 min) and AUC_(0-t) that a 0.3 mg intramuscular        injection yields;    -   a mean C_(max) that is at least 80% of the C_(max) and no more        than 150% of the C_(max) that a 0.3 mg intramuscular injection        yields;    -   a mean t_(max) of less than 45 minutes; and    -   IM-injection like absorption under optimal dosing conditions in        the thigh.

Embodiment 43b. In certain embodiments, the formulation comprisesbetween about 0.5 mg and about 1.15 mg per dose dispensed from thedevice of epinephrine, or a salt thereof, and when administered as anasal spray to a subject yields one or more of the followingpharmacokinetic features:

-   -   Both the mean AUC_(0-20 min) and AUC_(0-t) is at least 80% of        the AUC_(0-20 min) and AUC_(0-t) that a 0.15 mg intramuscular        injection yields;    -   A mean C_(max) that is at least 80% of the C_(max) and no more        than 150% of the C_(max) that a 0.15 mg intramuscular injection        yields;    -   A mean t_(max) of less than 45 minutes    -   IM-injection like absorption under optimal dosing conditions in        the thigh.

Embodiment 43c. In certain embodiments, the formulation comprisesbetween about 1.0 mg and about 2.0 mg per dose dispensed from the deviceof epinephrine, or a salt thereof, and when administered as a nasalspray to a subject yields one or more of the following pharmacokineticfeatures:

-   -   both the mean AUC_(0-20 min) and AUC_(0-t) are at least 80% of        the AUC_(0-20 min) and AUC_(0-t) that a 0.5 mg intramuscular        injection yields;    -   a mean C_(max) that is at least 80% of the C_(max) and no more        than 150% of the C_(max) that a 0.5 mg intramuscular injection        yields;    -   a mean t_(max) of less than 45 minutes; and    -   IM-injection like absorption under optimal dosing conditions in        the thigh.

Also provided are embodiments wherein any of Embodiments 43a, 43b, and43c comprise one or more of the limitations recited above in Embodiments2-22 and 30-42.

Also provided herein is Embodiment 44, a nasal spray formulationcomprising epinephrine, or a salt thereof, which when administered to asubject, yields one or more of the following pharmacokinetic features:

-   -   both the mean AUC_(0-20 min) and AUC_(0-t) are at least 80% of        the AUC_(0-20 min) and AUC_(0-t) that a 0.3 mg intramuscular        injection yields;    -   a mean C_(max) that is at least 80% of the C_(max) and no more        than 150% of the C_(max) that a 0.3 mg intramuscular injection        yields;    -   a mean t_(max) of less than 45 minutes; and    -   IM-injection like absorption under optimal dosing conditions in        the thigh.

Also provided herein is Embodiment 45, a nasal spray formulationcomprising epinephrine, or a salt thereof, which when administered to asubject, yields one or more of the following pharmacokinetic features:

-   -   both the mean AUC_(0-20 min) and AUC_(0-t) are at least 80% of        the AUC_(0-20 min) and AUC_(0-t) that a 0.15 mg intramuscular        injection yields;    -   a mean C_(max) that is at least 80% of the C_(max) and no more        than 150% of the C_(max) that a 0.15 mg intramuscular injection        yields;    -   a mean t_(max) of less than 45 minutes; and    -   IM-injection like absorption under optimal dosing conditions in        the thigh,

Also provided herein is Embodiment 46, a nasal spray formulationcomprising epinephrine, or a salt thereof, which when administered to asubject, yields one or more of the following pharmacokinetic features:

-   -   both the mean AUC_(0-20 min) and AUC_(0-t) are at least 80% of        the AUC_(0-20 min) and AUC_(0-t) that a 0.5 mg intramuscular        injection yields;    -   a mean C_(max) that is at least 80% of the C_(max) and no more        than 150% of the C_(max) that a 0.5 mg intramuscular injection        yields;    -   a mean t_(max) of less than 45 minutes; and    -   IM-injection like absorption under optimal dosing conditions in        the thigh.

Embodiment 47. The nasal spray formulation as recited in any ofEmbodiments 45-46, comprising between about 0.4 mg and about 2.40 mg perdose dispensed from the device of epinephrine, or a salt thereof.

Embodiment 48. The nasal spray formulation as recited in Embodiment 47,wherein the formulation is a pharmaceutical formulation.

Embodiment 49. The nasal spray formulation as recited in Embodiment 48,wherein the epinephrine or salt thereof is present in the pharmaceuticalformulation in an amount efficacious for the treatment of an acutehypersensitivity reaction.

Embodiment 50. The nasal spray formulation as recited in any ofEmbodiments 44-49, wherein the formulation is aqueous.

Embodiment 51. The nasal spray formulation as recited in any ofEmbodiments 44-50, wherein the formulation has intramuscular(IM)-injection-like or subcutaneous (SQ)-like absorption.

Embodiment 52. The nasal spray formulation as recited in Embodiment 51,wherein the formulation has intramuscular (IM)-injection-likeabsorption.

Embodiment 53. The nasal spray formulation as recited in Embodiment 51,wherein the formulation has subcutaneous (SQ)-like absorption.

Embodiment 54. The nasal spray formulation as recited in Embodiment 1-51where the SC pharmacokinetic profile has a C_(max) of at least 100 pg/mLand AUC_(0-240 min) of 150 h*pg/mL.

Embodiment 55. The nasal spray formulation as recited in any ofEmbodiments 44-54, wherein the formulation comprises between about 5mg/mL and about 40 mg/mL of epinephrine, or a salt thereof.

Embodiment 56. The nasal spray formulation as recited in any ofEmbodiments 44-55, wherein the formulation comprises between about 0.9mg and about 2.4 mg per dose dispensed from the device of epinephrine,or a salt thereof.

Embodiment 57. The nasal spray formulation as recited in any ofEmbodiments 44-55, wherein the formulation comprises between about 0.5mg and about 2.0 mg per dose dispensed from the device of epinephrine,or a salt thereof.

Embodiment 58. The nasal spray formulation as recited in any ofEmbodiments 44-55, wherein, the formulation comprises between about 0.75mg and about 1.5 mg per dose dispensed from the device of epinephrine,or a salt thereof.

Embodiment 59. The nasal spray formulation as recited in any ofEmbodiments 44-55, wherein the formulation comprises between about 0.9mg and about 1.15 mg per dose dispensed from the device of epinephrine,or a salt thereof.

Embodiment 60. The nasal spray formulation as recited in any ofEmbodiments 44-55, wherein the formulation comprises about 1.0 mg perdose dispensed from the device of epinephrine, or a salt thereof.

Embodiment 61. The nasal spray formulation as recited in any ofEmbodiments 44-55, wherein the formulation comprises between about 0.45mg and about 1.15 mg per dose dispensed from the device of epinephrine,or a salt thereof.

Embodiment 62. The nasal spray formulation as recited in any ofEmbodiments 44-55, wherein the formulation comprises between about 0.5mg and about 2.0 mg per dose dispensed from the device of epinephrine,or a salt thereof.

Embodiment 63. The nasal spray formulation as recited in any ofEmbodiments 44-55, wherein the formulation comprises about 0.5 mg perdose dispensed from the device of epinephrine, or a salt thereof.

Embodiment 64. The nasal spray formulation as recited in any ofEmbodiments 44-55, wherein the formulation comprises about 0.75 mg perdose dispensed from the device of epinephrine, or a salt thereof.

Embodiment 65. The nasal spray formulation as recited in any ofEmbodiments 44-55, wherein the formulation comprises about 1.0 mg perdose dispensed from the device of epinephrine, or a salt thereof.

Embodiment 66. The nasal spray formulation as recited in any ofEmbodiments 44-55, wherein the formulation comprises about 1.5 mg perdose dispensed from the device of epinephrine, or a salt thereof.

Embodiment 67. The nasal spray formulation as recited in any ofEmbodiments 44-66, wherein the formulation comprises less than one molarequivalents of acid to each mole of epinephrine.

Embodiment 68. The nasal spray formulation as recited in any ofEmbodiments 44-66, wherein the formulation comprises between about 0.5and about 1.1 molar equivalents of acid to each mole of epinephrine.

Embodiment 69. The nasal spray formulation as recited in either ofEmbodiments 66 and 67, wherein the acid is a strong acid. Strong acidsinclude hydrochloric acid, phosphoric acid, and sulfuric acid.

Embodiment 70. The nasal spray formulation as recited in Embodiment 69,wherein the acid is hydrochloric acid.

Embodiment 71. The nasal spray formulation as recited in any ofEmbodiments 44-70, wherein no base is added to the formulation duringits preparation.

Embodiment 72. The nasal spray formulation as recited in any ofEmbodiments 44-71, wherein the formulation has a pH between about 3.0and about 6.0. Alternative embodiment Embodiment 72. The nasal sprayformulation as recited in any of Embodiments 44-71, wherein theformulation has a pH between about 2.0 and about 6.0.

Embodiment 73. The nasal spray formulation as recited in Embodiment 72,wherein the formulation has a pH between about 3.5 and about 5.0.

Embodiment 74. The nasal spray formulation as recited in Embodiment 72,wherein the formulation has a pH between about 4.0 and about 4.5.

Embodiment 75. The nasal spray formulation as recited in Embodiment 72,wherein the formulation has a pH of about 4.5.

Embodiment 76. The nasal spray formulation as recited in Embodiment 72,wherein the formulation has a pH of about 4.0.

Embodiment 77. The nasal spray formulation as recited in any ofEmbodiments 44-76, wherein the formulation additionally comprises astabilizing agent.

Embodiment 78. The nasal spray formulation as recited in Embodiment 77,wherein the stabilizing agent is ethylenediaminetetraacetic acid (EDTA)or a salt thereof.

Embodiment 79. The nasal spray formulation as recited in Embodiment 78,wherein the EDTA is disodium EDTA.

Embodiment 80. The nasal spray formulation as recited in Embodiment 78,wherein the EDTA is present in an amount that is from 5% to 15% of theamount of the epinephrine, both measured in mmol. Alternative Embodiment80. The nasal spray formulation as recited in Embodiment 78, wherein theEDTA is present in an amount that is from about 0.001% (w/v) to about 1%(w/v).

Embodiment 81. The nasal spray formulation as recited in Embodiment 79,wherein the mmol of EDTA is about 10% of the mmol of the epinephrine.

Embodiment 82. The nasal spray formulation as recited in any ofEmbodiments 44-81, wherein the formulation additionally comprises apreservative.

Embodiment 83. The nasal spray formulation as recited in Embodiment 82,wherein the preservative is benzalkonium chloride.

Embodiment 84. The nasal spray formulation as recited in any ofEmbodiments 44-83, wherein the formulation additionally comprises anabsorption enhancer. In alternative Embodiment 84, The nasal sprayformulation as recited in any of Embodiments 44-83, wherein theformulation additionally comprises one or more absorption enhancers.

Embodiment 85. The nasal spray formulation as recited in Embodiment 84,wherein the absorption enhancer is an alkylsaccharide. In alternativeEmbodiment 85, The nasal spray formulation as recited in Embodiment 84,wherein the absorption enhancer is an alkylsaccharide and/orbenzalkonium chloride.

Embodiment 86. The nasal spray formulation as recited in Embodiment 85,wherein the absorption enhancer is dodecyl maltoside. In alternativeEmbodiment 86, The nasal spray formulation as recited in Embodiment 85,wherein the absorption enhancer is dodecyl maltoside, benzalkoniumchloride, or a combination of dodecyl maltoside and benzylalkoniumchloride.

Embodiment 87. The nasal spray formulation as recited in Embodiment 86,wherein the formulation comprises about 0.005% (w/v) to about 2.5% (w/v)dodecyl maltoside.

Embodiment 88. The nasal spray formulation as recited in Embodiment 87,wherein the formulation comprises about 0.1% (w/v) to about 0.5% (w/v)dodecyl maltoside.

Embodiment 89. The nasal spray formulation as recited in Embodiment 88,wherein the formulation comprises about 0.25% (w/v) dodecyl maltoside.Also provided is Embodiment 90, a method of treatment of a conditionmediated by adrenergic receptors comprising the intranasaladministration of the formulation as recited in any of Embodiments 1-89above.

Embodiment 91. The method as recited in Embodiment 90, wherein thecondition is chosen from a type-1 hypersensitivity reaction (systemicallergic reaction), an acute asthmatic attack, cardiac arrest, andStokes-Adams Syndrome.

Embodiment 92. The method as recited in Embodiment 91, wherein thecondition is a type-1 hypersensitivity reaction (systemic allergicreaction).

Embodiment 93. The method as recited in Embodiment 92, wherein thetype-1 hypersensitivity reaction (systemic allergic reaction) is chosenfrom allergic asthma, allergic conjunctivitis, allergic rhinitis,anaphylaxis, angioedema, urticaria, eosinophilia, drug allergy and foodallergy.

Embodiment 94. The method as recited in Embodiment 93, wherein the drugallergy is an antibiotic allergy.

Embodiment 95. Also provided herein is a method of treatment of asystemic allergic reaction and anaphylaxis comprising the intranasaladministration of an unbuffered intranasal formulation of epinephrine inan amount less than about 2.0 mg.

Also provided are embodiments wherein Embodiment 95 comprises one ormore of the limitations recited above in Embodiments 2-22, 25-28, 30-55,58-61, and 63-89.

Embodiment 96. A pharmaceutical composition comprising: a) epinephrine;and b) an alkylglycoside; wherein the composition is formulated foradministration into the circulatory system of a subject via theintranasal, inhalation, or pulmonary administration route. AlternativeEmbodiment 96. A pharmaceutical composition comprising: a) epinephrine;and b) an alkylglycoside; wherein the composition is a liquid formulatedfor intranasal delivery.

Embodiment 97. The pharmaceutical composition of Embodiment 96, whereinthe alkylglycoside has an alkyl chain including between 8 to 20 carbons.

Embodiment 98. The pharmaceutical composition of Embodiment 97, whereinthe alkylglycoside is selected from the group consisting of undecylmaltoside, dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside,sucrose mono-dodecanoate, sucrose mono-tridecanoate, and sucrosemono-tetradecanoate.

Embodiment 99. The pharmaceutical composition of Embodiment 98, whereinthe alkylglycoside is dodecyl-beta-D-maltoside.

Embodiment 100. The pharmaceutical composition of Embodiment 96, whereinthe alkylglycoside concentration is between about 0.001% and 10.0%(w/v).

Embodiment 101. The pharmaceutical composition of Embodiment 100,wherein the alkylglycoside concentration is between about 0.05% and 0.5%(w/v).

Embodiment 102. The pharmaceutical composition of Embodiment 96, whereinthe composition further comprises a membrane penetration-enhancingagent. The pharmaceutical composition of Embodiment 96, wherein thecomposition further comprises a membrane penetration-enhancing agent, pHmodifier, buffering agents, isotonicity agent, antioxidant, chelator,preservative, or a combination thereof.

Embodiment 103. The pharmaceutical composition of Embodiment 102,wherein the membrane penetration-enhancing agent is a surfactant, a bilesalt, a phospholipid, an alcohol, an enamine, a medium and/or long-chainamphipathic molecule, a small hydrophobic molecule, sodium or asalicylic acid derivative, a glycerol ester of acetoacetic acid, acyclodextrin, a medium-chain or long chain fatty acid, a chelatingagent, an amino acid or salt thereof, an enzyme or combination thereof.

Embodiment 104. The pharmaceutical composition of Embodiment 102,wherein the membrane penetration-enhancing agent is selected from thegroup consisting of citric acid, sodium citrate, propylene glycol,glycerin, ascorbic acid, sodium metabisulfite,ethylenediaminetetraacetic acid (EDTA) disodium, benzalkonium chloride,sodium hydroxide, and combinations thereof.

Embodiment 105. The pharmaceutical composition of Embodiment 102,wherein the membrane penetration-enhancing agent is benzalkoniumchloride, EDTA, or a combination thereof.

Embodiment 106. The pharmaceutical composition of Embodiment 96, whereinthe composition provides a Cmax for the epinephrine in a subject that isabout 2 fold or greater as compared to administration withoutalkylglycoside.

Embodiment 107. The pharmaceutical composition of Embodiment 96, whereinthe composition provides a Tmax for the epinephrine in a subject that isabout 2 fold or less as compared to administration withoutalkylglycoside.

Embodiment 108. The pharmaceutical composition of Embodiment 96, whereinthe composition provides a Tmax for the epinephrine of about 0.3 hoursor less in a subject.

Embodiment 109. The pharmaceutical composition of Embodiment 96, whereinthe composition has a pH of about 2.0 to 5.0.

Embodiment 110. A method of increasing the bioavailability ofepinephrine in a subject comprising administering to a subject acomposition comprising epinephrine and an alkylglycoside, therebyincreasing the bioavailability of the epinephrine in the subject,wherein the composition is administered into the circulatory system ofthe subject via the intranasal, inhalation, or pulmonary administrationroute. Alternative Embodiment 110. A method of increasing thebioavailability of epinephrine in a subject comprising administering toa subject a composition comprising epinephrine and an alkylglycoside,thereby increasing the bioavailability of the epinephrine in thesubject, wherein the composition is a liquid composition administeredintranasally.

Embodiment 111. The method of Embodiment 110, wherein the alkylglycosidehas an alkyl chain including between 8 to 20 carbons.

Embodiment 112. The method of Embodiment 111, wherein the alkylglycosideis selected from the group consisting of undecyl maltoside, dodecylmaltoside, tridecyl maltoside, tetradecyl maltoside, sucrosemono-dodecanoate, sucrose mono-tridecanoate, and sucrosemono-tetradecanoate.

Embodiment 113. The method of Embodiment 112, wherein the alkylglycosideis dodecyl-beta-D-maltoside.

Embodiment 114. The method of Embodiment 110, wherein the alkylglycosideconcentration is between about 0.001% and 10.0% (w/v).

Embodiment 115. The method of Embodiment 114, wherein the alkylglycosideconcentration is between about 0.05% and 0.5% (w/v).

Embodiment 116. The method of Embodiment 110, wherein the compositionfurther comprises a membrane penetration-enhancing agent.

Embodiment 117. The method of Embodiment 116, wherein the membranepenetration-enhancing agent is a surfactant, a bile salt, aphospholipid, an alcohol, an enamine, a long-chain amphipathic molecule,a small hydrophobic molecule, sodium or a salicylic acid derivative, aglycerol ester of acetoacetic acid, a cyclodextrin, a medium-chain fattyacid, a chelating agent, an amino acid or salt thereof, an enzyme orcombination thereof.

Embodiment 118. The method of Embodiment 117, wherein the membranepenetration-enhancing agent is selected from the group consisting ofcitric acid, sodium citrate, propylene glycol, glycerin, ascorbic acid,sodium metabisulfite, ethylenediaminetetraacetic acid (EDTA) disodium,benzalkonium chloride, sodium hydroxide, and combinations thereof.

Embodiment 119. The method of Embodiment 116, wherein the membranepenetration-enhancing agent is benzalkonium chloride, EDTA, or acombination thereof.

Embodiment 120. The method of Embodiment 110, wherein the compositionprovides a Cmax for the epinephrine in the subject that is about 2 foldor greater as compared to administration without alkylglycoside.

Embodiment 121. The method of Embodiment 110, wherein the compositionprovides a Tmax for the epinephrine in the subject that is about 2 foldor less as compared to administration without alkylglycoside.

Embodiment 122. The method of Embodiment 110, wherein the compositionprovides a Tmax for the epinephrine of about 0.3 hours or less in thesubject.

Embodiment 123. The method of Embodiment 110, wherein the compositionhas a pH of about 2.0 to 6.0. Alternative Embodiment 123. The method ofEmbodiment 110, wherein the composition has a pH of about 2.0 to 5.0.

Definitions

As used herein, the following terms have the meanings indicated.

When ranges of values are disclosed, and the notation “from n₁ . . . ton₂” or “between n₁ . . . and n₂” is used, where n₁ and n₂ are thenumbers, then unless otherwise specified, this notation is intended toinclude the numbers themselves and the range of numbers between them.This range may be integral or continuous between and including the endvalues. By way of example, the range “from 2 to 6 carbons” is intendedto include two, three, four, five, and six carbons, since carbons comein integer units. Compare, by way of example, the range “from 1 to 3 μM(micromolar),” which is intended to include 1 μM, 3 μM, and everythingin between to any number of significant figures (e.g., 1.255 μM, 2.1 μM,2.9999 μM, etc.).

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within arange. When no range, such as a margin of error or a standard deviationto a mean value given in a chart or table of data, is recited, the term“about” should be understood to mean the greater of the range whichwould encompass the recited value and the range which would be includedby rounding up or down to that figure as well, considering significantfigures, and the range which would encompass the recited value plus orminus 20%.

“Weight per volume” or “w/v” refers to the mass in grams of a dissolvedsolute divided by the volume in milliliters of the entire solution.Typically, weight by volume is expressed as a percentage.

The term “absorption enhancer,” as used herein, refers to a functionalexcipient included in formulations to improve the absorption of anactive agent such as a pharmacologically active drug. This term usuallyrefers to an agent whose function is to increase absorption by enhancingnasal mucous-membrane permeation, rather than increasing solubility. Assuch, such agents are sometimes called permeation enhancers orpenetration enhancers. In particular, absorption enhancers describedherein may improve paracellular transport (i.e., passage throughintercellular spaces and tight junctions), transcellular transport(i.e., passive diffusion or active transport across cellular membranes),or transcytosis (i.e., cellular vesicular uptake). Ozsoy et al.,Molecules 14:3754-79, 2009.

Examples of absorption enhancers include alcohol, aprotinin,benzalkonium chloride, benzyl alcohol, capric acid, ceramides,cetylpyridinium chloride, chitosan, cyclodextrins, deoxycholic acid,decanoyl, dimethyl sulfoxide, glyceryl monooleate, glycofurol,glycofurol, glycosylated sphingosines, glycyrrhetinic acids,2-hydroxypropyl-β-cyclodextrin, laureth-9, lauric acid, lauroylcarnitine, sodium lauryl sulfate, lysophosphatidylcholine, menthol,poloxamer 407 or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether,isopropyl myristate, isopropyl palmitate, lanolin, light mineral oil,linoleic acid, menthol, myristic acid, myristyl alcohol, oleic acid, orsalt thereof, oleyl alcohol, palmitic acid, polysorbate 80, propyleneglycol, polyoxyethylene alkyl ethers, polyoxylglycerides, pyrrolidone,quillaia saponin, salicylic acid, sodium salt, β-sitosterolβ-D-glucoside, sucrose cocoate, taurocholic acid, taurodeoxycholic acid,taurodihydrofusidic acid, thymol, tricaprylin, triolein, andalkylsaccharides, and combinations thereof, including but not limited tododecyl maltoside, dodecyl-β-D-maltoside, tetradecyl maltoside,tetradecyl-β-D-maltoside and sucrose dodecanoate. Alkylsaccharides(e.g., nonionic alkylsaccharide surfactants such as alkylglycosides andsucrose esters of fatty acids that consist of an aliphatic hydrocarbonchain coupled to a sugar moiety by a glycosidic or ester bond,respectively), cyclodextrins (cyclic oligosaccharides composed of six ormore monosaccharide units with a central cavity, which form inclusioncomplexes with hydrophobic molecules and they have primarily been usedto increase drug solubility and dissolution and to enhance low molecularweight drug absorption), chitosans (linear cationic polysaccharidesproduced from the deacetylation of chitin), and bile salts and theirderivatives (such as sodium glycocholate, sodium taurocholate, andsodium taurodihydrofusidate) tend to be amongst the best-toleratedabsorption enhancers. See, e.g., Aungst B J, AAPS Journal 14(1):10-8,2011; and Maggio, ET, Excipients and Food Chem. 5(2):100-12, 2014. Dueto their chemical properties, certain absorption enhancers can functionas preservatives and/or cationic surfactants in certain circumstances,depending on concentration in the formulation and other factors.

Described herein are compositions comprising epinephrine and at leastone absorption enhancer and/or preservative and/or surfactant whereinthe at least one absorption enhancer and/or preservative and/orsurfactant comprises at least one alkylglycoside and/or at least onesaccharide alkyl ester.

As used herein, the term “alkylsaccharide” (also referred to herein as“alkylglycoside”) refers to a type of an absorption enhancer. As usedherein, an alkylsaccharide refers to any sugar joined by a linkage toany hydrophobic alkyl, as is known in the art. Alkylsaccharides include,but are not limited to: alkylsaccharides, such as octyl-, nonyl-,decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-,hexadecyl-, heptadecyl-, and octadecyl-α- or β-D-maltoside, -glucosideor -sucroside; alkyl thiomaltosides, such as heptyl, octyl, dodecyl-,tridecyl-, and tetradecyl-β-D-thiomaltoside; alkyl thioglucosides, suchas heptyl- or octyl 1-thio α- or β-D-glucopyranoside; alkylthiosucroses; alkyl maltotriosides; long chain aliphatic carbonic acidamides of sucrose (3-amino-alkyl ethers; derivatives of palatinose andisomaltamine linked by amide linkage to an alkyl chain; derivatives ofisomaltamine linked by urea to an alkyl chain; long chain aliphaticcarbonic acid ureides of sucrose β-amino-alkyl ethers; and long chainaliphatic carbonic acid amides of sucrose β-amino-alkyl ethers. Thehydrophobic alkyl can be chosen of any desired size, depending on thehydrophobicity desired and the hydrophilicity of the saccharide moiety.For example, one preferred range of alkyl chains is from about 9 toabout 24 carbon atoms. An even more preferred range is from about 9 toabout 16 or about 14 carbon atoms. Similarly, some preferred saccharidesinclude maltose, sucrose, and glucose linked by glycosidic linkage to analkyl chain of 9, 10, 12, 13, 14, 16, 18, 20, 22, or 24 carbon atoms,e.g., nonyl-, decyl-, dodecyl- and tetradecyl sucroside, glucoside, andmaltoside, etc. The alkyl chain of an alkylsaccharide is often linked tothe saccharide via a glycosidic bond, and accordingly, alkylsaccharidesare often interchangeably referred to as alkylglycosides.

Any “suitable” alkylglycoside means one that fulfills thecharacteristics contemplated herein, i.e., that the alkylglycoside benontoxic and nonionic, and that it increases the absorption of acompound (e.g. epinephrine) when it is administered with the compoundvia the nasal delivery route.

As use herein, a “saccharide” is inclusive of monosaccharides,oligosaccharides or polysaccharides in straight chain or ring forms, ora combination thereof to form a saccharide chain. Oligosaccharides aresaccharides having two or more monosaccharide residues. The saccharidecan be chosen, for example, from any currently commercially availablesaccharide species or can be synthesized. Some examples of the manypossible saccharides to use include glucose, maltose, maltotriose,maltotetraose, sucrose and trehalose. Preferable saccharides includemaltose, sucrose and glucose.

In some embodiments, described herein are composition that include atleast one alkylglycoside and/or saccharide alkyl ester and epinephrine,methods of administering and using the compositions via the nasaldelivery route, and methods of ameliorating a disease state in a subjectby administration of such compositions.

In some embodiments, described herein is a method of administering acomposition having at least one alkylglycoside and/or saccharide alkylester admixed, mixed, or blended with epinephrine and administered ordelivered to a subject, wherein the alkyl has from about 10 to 24, 10 to20, 10 to 16, or 10 to 14 carbon atoms, wherein the at least onealkylglycoside and/or saccharide alkyl ester increases the stability andbioavailability of the therapeutic agent.

In some embodiments, alkylsaccharides contemplated have a hydrophobicalkyl group linked to a hydrophilic saccharide. The linkage between thehydrophobic alkyl group and the hydrophilic saccharide can include,among other possibilities, a glycosidic, thioglycosidic (Horton), amide(Carbohydrates as Organic Raw Materials, F. W. Lichtenthaler ed., VCHPublishers, New York, 1991), ureide (Austrian Pat. 386,414 (1988); Chem.Abstr. 110:137536p (1989); see Gruber, H. and Greber, G., “ReactiveSucrose Derivatives” in Carbohydrates as Organic Raw Materials, pp.95-116) or ester linkage (Sugar Esters: Preparation and Application, J.C. Colbert ed., (Noyes Data Corp., New Jersey), (1974)). Further,preferred glycosides can include maltose, sucrose, and glucose linked byglycosidic linkage to an alkyl chain of about 9-16 carbon atoms, e.g.,nonyl-, decyl-, dodecyl- and tetradecyl sucroside, glucoside, andmaltoside. These compositions are amphipathic and nontoxic, because theydegrade to an alcohol and an oligosaccharide.

The above examples are illustrative of the types of glycosidescontemplated, but the list is not exhaustive. Derivatives of the abovecompounds which fit the criteria described herein are also contemplatedwhen choosing an alkylsaccharide.

In some embodiments, membrane penetration-enhancing agents contemplatedserve as anti-bacterial agents. An agent is an “anti-bacterial” agent orsubstance if the agent or its equivalent destroy bacteria, or suppressbacterial growth or reproduction.

The term “active ingredient” or “pharmaceutically active compound” isdefined in the context of a “formulation” and is intended to mean acomponent of a pharmaceutical formulation that provides the primarypharmacological effect, as opposed to an “inactive ingredient” whichwould generally be recognized as providing no pharmaceutical benefit.

The term “actuation,” as used herein, refers to operation of the devicesuch that the pharmaceutical formulation is delivered therefrom.

The term “antimicrobial preservative,” as used herein, refers to apharmaceutically acceptable excipient with antimicrobial propertieswhich is added to a pharmaceutical formulation to maintainmicrobiological stability. Antimicrobial preservatives include, but arenot limited to, antibacterial agents, antifungal agents, antioxidants,and preservatives.

The term “AUC,” as used herein, refers to the area under the drug plasmaconcentration-time curve. The term “AUC_(0-t),” as used herein, refersto the area under the drug plasma concentration-time curve from t=0 tothe last measured or measurable concentration. The term “AUC_(0-∞),” orequivalently, “AUC_(0-inf),” as used herein, refers to the area underthe drug plasma concentration-time curve extrapolated to infinity (Go).

As used here, the term “benzalkonium chloride” (“BZK”) refers to amember of the class of quaternary ammonium compounds having thefollowing structure:

in which n is an integer. Benzalkonium chloride is a mixture ofalkylbenzyl dimethylammonium chlorides, where a mixture of more than onen is used. In certain embodiments, n is 8, 10, 12, 14, 16, or 18. Inother embodiments, n is 10, 12, or 14. In some embodiments, a mixture ofn is 10, 12 and/or 14 predominate. In some embodiments, a mixture of nis 10, 12, 14 and/or 16 predominate. In some embodiments, benzalkoniumchloride functions as a preservative (even in low amounts), anantiseptic, a disinfectant, a solubilizing and wetting agent, and/or acationic surfactant. In some cases, benzalkonium chloride refers to atype of an absorption enhancer.

The term “bioavailability (F),” as used herein, refers to the fractionof a dose of drug that is absorbed from its site of administration andreaches, in an unchanged form, the systemic circulation. The term“absolute bioavailability” is used when the fraction of absorbed drug isrelated to its IV bioavailability. It may be calculated using thefollowing formula:

$F = {\frac{{AUC}_{extravascular}}{{AUC}_{intravenous}} \times \frac{{Dose}_{intravenous}}{{Dose}_{extravascular}}}$

The term “relative bioavailability (Frei)” is used to compare twodifferent extravascular routes of drug administration and it may becalculated using the following formula:

$F_{rel} = {\frac{{AUC}_{{extravascular}1}}{{AUC}_{{extravascular}2}} \times \frac{{Dose}_{{extravascular}2}}{{Dose}_{{extravascular}1}}}$

The term “clearance (CL),” as used herein, refers to the rate at which adrug is eliminated divided by its plasma concentration, giving a volumeof plasma from which drug is completely removed per unit of time. CL isequal to the elimination rate constant (λ) multiplied by the volume ofdistribution (V_(d)), wherein “V_(d)” is the fluid volume that would berequired to contain the amount of drug present in the body at the sameconcentration as in the plasma. The term “apparent clearance (CL/F),” asused herein, refers to clearance that does not take into account thebioavailability of the drug. It is the ratio of the dose over the AUC.

The term “C_(max),” as used herein, refers to the maximum observedplasma concentration.

The term “coefficient of variation (CV),” as used herein, refers to theratio of the sample standard deviation to the sample mean. It is oftenexpressed as a percentage.

The term “confidence interval,” as used herein, refers to a range ofvalues which will include the true average value of a parameter aspecified percentage of the time.

The term “device,” as used herein, refers to an apparatus capable ofdelivering a drug to patient in need thereof.

The term “delivery time,” as used herein, refers to the amount of timethat elapses between a determination made by a healthcare professional,or an untrained individual that an individual is in need of nasaldelivery of epinephrine and completion of the delivery.

The term “disease,” as used herein, is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder,”“syndrome,” and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms, and causes the human or animal tohave a reduced duration or quality of life.

As used herein, the “dose dispensed from the device” is typicallymeasured in the nasal spray setting by the difference in weight of adevice before and after actuation to release a dose of the formulationcontained therein. The volume of liquid formulation and weight inmilligrams of the active moiety contained therein may be determined bystandard calculations.

The term “elimination rate constant (λ),” as used herein, refers to thefractional rate of drug removal from the body. This rate is constant infirst-order kinetics and is independent of drug concentration in thebody. λ is the slope of the plasma concentration-time line (on alogarithmic y scale). The term “λ_(z),” as used herein, refers to theterminal phase elimination rate constant, wherein the “terminal phase”of the drug plasma concentration-time curve is a straight line whenplotted on a semi-logarithmic graph. The terminal phase is often calledthe “elimination phase” because the primary mechanism for decreasingdrug concentration during the terminal phase is drug elimination fromthe body. The distinguishing characteristic of the terminal eliminationphase is that the relative proportion of drug in the plasma andperipheral volumes of distribution remains constant. During this“terminal phase” drug returns from the rapid and slow distributionvolumes to the plasma, and is permanently removed from the plasma bymetabolism or renal excretion.

The term “equal,” as used herein, means essentially the same as (i.e.,negligibly different from) in quantity, amount, value, degree, or size.The term “equal” may, in certain embodiments, include “bioequivalent,”but the terms are not coterminous.

The term “bioequivalent,” as used herein, describes the relationshipbetween a reference and a putative equivalent or alternative drug, andper 21 C.F.R. § 320.1, means that there is no significant difference inthe rate and extent to which the active ingredient or active moiety inpharmaceutical equivalents or pharmaceutical alternatives becomesavailable at the site of drug action when administered at the same molardose under similar conditions in an appropriately designed study. Rateand extent of absorption may be determined from, or informed by, C_(max)and AUC, respectively. In certain embodiments, statistical criteria maybe used, e.g., between 80% and 125% of a reference value, or 90% CI.

The term “molar equivalent,” as used herein, refers to an amount ofepinephrine that is equimolar to a specified amount of acid.

The term “excipient,” as used herein, refers to a natural or syntheticsubstance formulated alongside the active ingredient of a medication. Anexcipient is included in a formulation for a variety of reasons such as,but not limited to, long-term stabilization, bulking up solidformulations, or to confer a therapeutic enhancement on the activeingredient in the final dosage form, such as facilitating drugabsorption, reducing viscosity, or enhancing solubility.

The term “filled,” as used herein, refers to an association between adevice and a pharmaceutical formulation, for example, when apharmaceutical formulation described herein comprising a therapeuticallyeffective amount of epinephrine is present within a reservoir that formsa part of a device described herein.

The term “formulation,” with or without the modifier “pharmaceutical,”as used herein, refers to a composition comprising at least onephysiologically active ingredient (e.g., a drug); including but notlimited to, salts, solvates and hydrates of epinephrine and relatedcompounds described herein, whereby the formulation is amenable to usefor a specified, efficacious outcome in a mammal (for example, withoutlimitation, a human).

The term “pharmaceutical formulation,” as used herein, alone or incombination, refers to a formulation that is suited for use fortreatment (or in certain embodiments, prevention) of a disease in asubject.

The term “hydrate,” as used herein, refers to epinephrine describedherein or a salt thereof that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

The term “in need of treatment” and the term “in need thereof” whenreferring to treatment are used interchangeably and refer to a judgmentmade by a caregiver (e.g. physician, nurse, nurse practitioner, that apatient will benefit from treatment.

As used herein, an “intramuscular (IM) injection” of epinephrine istypically administered via an IM epinephrine delivered by auto injectorin the thigh, e.g., in the vestus lateralis muscle (referred to hereinas “optimal dosing conditions in the thigh”). As such, when comparingpharmacokinetic parameters yielded by IM epinephrine injection to thoseyielded by IN epinephrine administration, the comparison should beassumed to be as if the IM injection were in the thigh, which is theoptimal dosing method for epinephrine. In one embodiment, IM epinephrineinjection is achieved with EpiPen® Auto-Injector (0.3 mg/0.3 mLepinephrine injection, USP, pre-filled auto-injector; Mylan SpecialtyL.P.).

As used herein, an “subcutaneous (SQ) injection” of epinephrine istypically administered by injection into the subcutaneous layer of thedeltoid region in the upper arm. Simons et al. Epinephrine absorption inadults: Intramuscular versus subcutaneous injection. J Allergy. Clin.Immunol. 2001; 108:871-3.

As used herein, two embodiments are “mutually exclusive” when one isdefined to be something which is different than the other. For example,an embodiment wherein the concentration of epinephrine is specified tobe 5 mg/mL is mutually exclusive with an embodiment wherein the amountof epinephrine is specified to be 10 mg/mL. However, an embodimentwherein the amount of epinephrine is specified to be 5 mg/mL is notmutually exclusive with an embodiment in which less than about 10% ofthe pharmaceutical formulation leaves the nasal cavity via drainage intothe nasopharynx or externally.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent of a formulation, often referred to as a carrier or excipient,that is compatible with the other ingredients of the formulation and notoverly deleterious to the recipient thereof.

The term “pre-primed,” as used herein, refers to a device, such as anasal spray which can deliver a formulation to a patient in need thereofwith the first actuation of the spray pump, i.e., without the need toprime the pump prior to dosing, such as by actuating the pump one ormore times until a spray appears.

The term “prone,” as used herein, refers to a patient who is lying facedown.

As used herein, the term “protective packaging” refers to overwrap.

The term “solvate,” as used herein, refers to epinephrine describedherein or a salt, thereof, that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for administration to humans in trace amounts.

The term “storage-stable,” as used herein, refers to a formulation inwhich at least about 90% to 115% of the active ingredient remains withinacceptable regulatory specifications after storage of the formulation atspecified temperature and humidity for a specified time, for example,for at least 12 months at 25° C. and 60% relative humidity and about sixmonths at about 40° C. and about 75% relative humidity.

The term “subject,” as used herein, is intended to be synonymous with“patient,” and refers to any mammal (preferably human) afflicted with acondition likely to benefit from treatment with a therapeuticallyeffective amount epinephrine, e.g., a subject experiencing a type-1hypersensitivity reaction (systemic allergic reaction) such asanaphylaxis.

The term “supine,” as used herein, refers to a patient who is lying faceup.

The term “nostril,” as used herein, is synonymous with “naris.”

The term “therapeutically effective amount” or “therapeuticallyeffective dose,” as used herein, refers to the amount or dose of activecompound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, or individual that is beingsought by a researcher, healthcare provider or individual. Atherapeutically effective amount may, but need not necessarily,eliminate one, more, or all symptoms of a disease, disorder, orcondition being treated. A therapeutically effective amount may alsoprevent disease progression or the appearance of further symptoms.

The term “t_(1/2)” or “half-life,” as used herein, refers to the amountof time required for half of a drug or other analyte of interest (forexample, an adrenergic receptor agonist) to be eliminated from the bodyor the time required for a drug concentration to decline by half.

The term “tonicity agent,” as used herein, refers to a compound whichmodifies the osmolality of a formulation, for example, to render itisotonic. Tonicity agents include, dextrose, lactose, sodium chloride,calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol,trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycineand the like. In some embodiments, formulations contemplated hereininclude one or more tonicity agents selected from dextrose, glycerin,mannitol, potassium chloride and sodium chloride. In some embodiments,formulations contemplated herein include sodium chloride as a tonicityagent.

The term “tomography,” as used herein, refers to a process of imaging bysections. The images may be looked at individually, as a series oftwo-dimensional slices or together, as a computer-generatedthree-dimensional representation.

The term “T_(max),” as used herein, refers to the time, fromadministration, for a drug or other analyte to reach maximum drug plasmaconcentration (C_(max)).

Epinephrine

The term “epinephrine” as used herein refers to the compound(R)-4-(1-Hydroxy-2-(methylamino)ethyl)benzene-1,2-diol, also known asadrenaline, shown below and having the following structure, elementalmakeup, molecular weight, and CAS Registry Number:

The term include any metabolite, salt, ester, hydrate, anhydride,solvate, isomer, isotope, enantiomer, free acid form, free base form,crystalline form, co-crystalline form, complexes, amorphous form,pro-drug (including ester pro-drug) form, racemate, polymorph, chelate,isomer, tautomer, or optically active form thereof, or mixture of anytwo or more of the foregoing.

Provided are drug products adapted for nasal delivery of epinephrine,including formulations and devices. Epinephrine acts by binding to avariety of adrenergic receptors. Epinephrine is a nonselective agonistof all adrenergic receptors, including the major subtypes α1, α2, β1,β2, and β3. Its actions vary by tissue type and tissue expression ofadrenergic receptors. For example, high levels of epinephrine causessmooth muscle relaxation in the airways but causes contraction of thesmooth muscle that lines most arterioles.

Provided are formulations, devices adapted for nasal delivery of aformulation to a patient, kits comprising the foregoing, and methods ofusing the same in treatment, each comprising a therapeutically effectiveamount of epinephrine.

Epinephrine may be present in the formulations administered herein atconcentrations between 1 mg/mL and 40 mg/mL, for example, atconcentrations of about 5 mg/mL, about 10 mg/mL, or about 20 mg/mL.

Epinephrine may be present in the formulations administered herein atdoses between 0.1 mg and 4 mg, for example, at doses of about 0.5 mg,about 1.0 mg, or about 2.0 mg. These doses may be scaled based onmolecular weight of a counterion if a salt is used to prepare theformulation.

Epinephrine may optionally exist as a pharmaceutically acceptable saltincluding pharmaceutically acceptable acid addition salts prepared frompharmaceutically acceptable non-toxic acids including inorganic andorganic acids. Representative acids include, but are not limited to,acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic,hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic andthe like, such as those pharmaceutically acceptable salts listed byBerge et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977). Theacid addition salts may be obtained as the direct products of compoundsynthesis. In the alternative, the free base may be dissolved in asuitable solvent containing the appropriate acid and the salt isolatedby evaporating the solvent or otherwise separating the salt and solvent.Due to the perceived insolubility of epinephrine base, finished dosageforms of epinephrine used in healthcare (solutions, aerosols, etc.) aretypically salts, e.g. hydrochloride, bitartrate, or borate salts. Incertain embodiments, formulations contemplated herein include a saltform of epinephrine that is epinephrine acetate, epinephrinehydrochloride, epinephrine tartrate, epinephrine bitartrate, epinephrinehydrogen tartrate or epinephrine borate.

Accordingly, provided herein are pharmaceutical formulations forintranasal administration comprising epinephrine. In certainembodiments, the formulation is an aqueous solution. In certainembodiments, the formulation comprises, per dose, between about 25 andabout 250 μL of the aqueous solution. In certain embodiments, theformulation comprises, per dose, between about 50 and about 250 μL ofthe aqueous solution. In certain embodiments, the formulation comprises,per dose, between about 50 and about 200 μL of the aqueous solution. Incertain embodiments, the formulation comprises, per dose, not more thanabout 140 μL. In certain embodiments, the formulation comprises, perdose, not more than about 100 μL. In certain embodiments, theformulation comprises, per dose, about 100 μL. The formulation maycomprise, per dose, about 25 μL, about 50 μL, about 75 μL, about 100 μL,about 125 μL, about 150 μL, about 175 μL, about 200 μL, or about 250 μL,of the aqueous solution.

The pharmaceutical formulations for intranasal administration comprisingepinephrine described herein bypass potential metabolic conversion inthe gastrointestinal tract and hepatic first-pass metabolism, and reachthe systemic circulation in a pharmacologically active form. Epinephrineis extensively metabolized after oral administration by thecatechol-O-methyltransferase in the gastrointestinal tract and bymonoamine oxidase in the gastrointestinal tract and in the liver.Avoiding first pass clearance assures that more of the epinephrine thatis administered will be available to treat anaphylaxis. By avoidingfirst pass liver clearance, the bioavailability of the epinephrine isincreased.

Formulations

Also provided are pharmaceutical formulations comprising epinephrine.Certain embodiments of the present disclosure include a method ofproducing a formulation comprising admixing epinephrine and apharmaceutically acceptable carrier. Pharmaceutical formulations areapplied directly to the nasal cavity using the devices described herein.In the case of a spray, this may be achieved for example by means of ametering atomizing spray pump, e.g. a single, bi-dose or multiuse spraydevice, with or without a propellant.

Liquid preparations include solutions, suspensions and emulsions, forexample, water, or water-ethanol, or water-propylene glycol solutions.Typically, the formulation is an aqueous liquid solution. Additionalingredients in liquid preparations may include preservatives,stabilizing agents, tonicity agents, absorption enhancers, pH-adjustingagents, antioxidants, buffers, sweetners/flavoring agents/task-maskingagents, and optionally other ingredients. Ingredients in liquidpreparations may serve different functions. The function(s) of aparticular ingredient will depend on a number of factors including, butnot limited to, presence or absence of other ingredients,concentration(s), and other factors.

Preservatives include: benzalkonium chloride, methylparaben, sodiumbenzoate, benzoic acid, phenyl ethyl alcohol, and the like, and mixturesthereof. Due to their chemical properties, certain preservatives canfunction as a surfactants and/or absorption enhancers in certaincircumstances, depending on concentration in the formulation and otherfactors.

Other preservatives include: alcohol, benzalkonium chloride,benzethonium chloride, benzoic acid, benzyl alcohol, boric acid,bronopol, butylated hydroxyanisole (BHA), butylene glycol, butylparaben,calcium acetate, calcium chloride, calcium lactate, carbon dioxide,bentonite, cetrimide, cetylpyridinium chloride, chlorhexidine,chlorobutanol, chlorocresol, chloroxylenol, citric acid monohydrate,cresol, dimethyl ether, ethylparaben, glycerin, hexetidine, imidurea,magnesium trisilicate, isopropyl alcohol, lactic acid, methylparaben,monothioglycerol, parabens (methyl, ethyl and propyl), pentetic acid,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate,phenylmercuric borate, phenylmercuric nitrate, potassium benzoate,potassium metabisulfite, potassium sorbate, propionic acid, propylgallate, propylene glycol, propylparaben, propylparaben sodium, sodiumacetate, sodium benzoate, sodium borate, sodium lactate, sodiummetabisulfite, sodium propionate, sodium sulfite, sorbic acid,sulfobutyletherb-cyclodextrin, sulfur dioxide, edetic acid, thimerosal,and xylitol.

In some embodiments, preservatives include, but are not limited to,antibacterial agents, antifungal agents, and antioxidants.

Antibacterial agents include, but are not limited to, chlorocresol,diazolidinyl urea, dimethyl sulfoxide, glacial acetic acid, imidurea,iodine/edetic acid, phenylmercuric mercuric acetate, phenylmercuricborate, phenylmercuric hydroxide, potassium sorbate, sodium hydroxide,sorbic acid, thymol, antiseptics, and disinfectants.

Antifungal agents include, but are not limited to, benzoic acid,butylene butylparaben, chlorocresol, coconut oil, dimethyl sulfoxide,ethylparaben, glacial acetic acid, imidurea, methylparabens,phenylmercuric acetate, phenylmercuric borate, phenylmercuric hydroxide,potassium sorbate, propylparaben, sodium propionate, sodium thiosulfate,thymol, and vanillin.

Surfactants include but are not limited to: Polysorbate 80 NF,polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitanmonolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate,polyoxyethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitanmonooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20sorbitan monoisostearate, sorbitan monooleate, sorbitan monolaurate,sorbitan monopalmitate, sorbitan monostearate, sorbitan trilaurate,sorbitan trioleate, sorbitan tristearate, and the like, and mixturesthereof. Due to their chemical properties, certain surfactants canfunction as a preservatives and/or absorption enhancers in certaincircumstances, depending on concentration in the formulation and otherfactors.

Surfactants include but are not limited to: cationic, anionic, nonionicand zwitterionic surfactants.

Surfactants also include: anionic surfactants (e.g. carboxylatessulphonates, petroleum sulphonates, alkylbenzenesulphonates,naphthalenesulphonates, olefin sulphonates, alkyl sulphates, sulphates,sulphated natural oils and fats, sulphated esters, sulphatedalkanolamides, alkylphenols, ethoxylated and sulphated), nonionicsurfactants (e.g. ethoxylated aliphatic alcohol, polyoxyethylenesurfactants, carboxylic esters, polyethylene glycol esters,anhydrosorbitol ester and it's ethoxylated derivatives, glycol esters offatty acids, carboxylic amides, monoalkanolamine condensates,polyoxyethylene fatty acid amides), cationic surfactants (e.g.quaternary ammonium salts, amines with amide linkages, polyoxyethylenealkyl and alicyclic amines, 4.n,n,n′,n′ tetrakis substitutedethylenediamines, 2-alkyl 1-hydroxethyl 2-imidazolines), amphotericsurfactants (amphoteric surfactants contains both an acidic and a basichydrophilic moiety in their surface e.g., n-coco 3-aminopropionicacid/sodium salt, n-tallow 3-iminodipropionate, disodium salt,n-carboxymethyl n dimethyl n-9 octadecenyl ammonium hydroxide,n-cocoamidethyl n hydroxyethylglycine, sodium salt, etc.).

Antioxidants include, but are not limited to, tocopherol, arachidonicacid, ascorbic acid, ascorbyl palmitate, benzethonium chloride,benzethonium bromide, benzalkonium chloride, butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), capric acid, caproic acid, carbondioxide, cetylpyridium chloride, chelating agents, chitosan derivatives,citric acid monohydrate, dodecyl dimethyl aminopropionate, enanthicacid, erythorbic acid, ethyl oleate, fumaric acid, glycerol oleate,glyceryl monostearate, lauric acid, limonene, linolenic acid, lysine,malic acid, menthol, methionine, monothioglycerol, myristic acid, oleicacid, or salt thereof, palmitic acid, pelargonic acid, peppermint oil,phosphoric acid, polysorbates, potassium metabisulfite, propionic acid,propyl gallate, sodium ascorbate, sodium bisulfate, sodium caprate,sodium desoxycholate, sodium deoxyglycolate, sodium formaldehydesulfoxylate, sodium glycocholate, sodium hydroxybenzoyal aminocaprylate, sodium lauryl sulfate, sodium metabisulfite, sodium sulfite,sodium taurocholate, sodium thiosulfate, stearic acid, sulfur dioxideand a combination thereof.

Buffers include, but are not limited to, phosphate buffers, acetatebuffers, and citrate buffers.

In some embodiments, the nasal spray formulation comprises a bufferingagent. Buffering agents include, but are not limited to, adipicacid,boric acid, calcium carbonate, calcium hydroxide, calcium lactate,calcium phosphate, tribasic, citric acid monohydrate, dibasic sodiumphosphate, diethanolamine, glycine, maleic acid, malic acid, methionine,monobasic sodium phosphate, monoethanolamine, monosodium glutamate,phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate,sodium borate, sodium carbonate, sodium citrate dihydrate, sodiumhydroxide, sodium lactate, and triethanolamine.

Isotonicity agents include sodium chloride, calcium chloride, magnesiumchloride, sorbitol, sucrose, dextrose, lactose, mannitol, trehalose,raffinose, polyethylene glycol, hydroxyethyl starch, glycerine, glycine,and the like, and mixtures thereof. In certain embodiments, theisotonicity agent is chosen from dextrose, glycerin, mannitol, potassiumchloride, and sodium chloride. In certain embodiments, the isotonicityagent is sodium chloride. In certain embodiments, the formulationsdisclosed herein contain sodium chloride in an amount sufficient tocause the final composition to have a nasally acceptable osmolality,preferably 240-350 mOsm/kg. In certain embodiments, the formulationscontain 0.3-1.9% sodium chloride.

Sweetners/flavoring agents/task-masking agents include, but are notlimited to, sucrose, dextrose, lactose, sucralose, acesulfame-K,aspartame, saccharin, sodium saccharin, citric acid, aspartic acid,eucalyptol, mannitol, glycerin, xylitol, menthol, glycyrrhizic acid,cinnamon oils, oil of wintergreen, peppermint oils, clover oil, bay oil,anise oil, eucalyptus, vanilla, citrus oil such as lemon oil, orangeoil, grape and grapefruit oil, fruit essences including apple, peach,pear, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. andcombinations thereof. In some embodiments, the formulations contain fromabout 0.0001 percent to about 1 percent of a sweetner/flavoringagent/task-masking agent, and may be present at lower or higher amountsas a factor of one or more of potency of the effect on flavor,solubility of the flavorant, effects of the flavorant on solubility orother physicochemical or pharmacokinetic properties of other formulationcomponents, or other factors.

In certain embodiments, the pharmaceutical formulation additionallycomprises an isotonicity agent. The intranasal formulation may comprisebetween about 0.2% (w/v) and about 1.2% (w/v) isotonicity agent, such asabout 0.2% (w/v), about 0.3% (w/v), about 0.4% (w/v), about 0.5% (w/v),about 0.6% (w/v), about 0.7% (w/v), about 0.8% (w/v), about 0.9% (w/v),about 1.0% (w/v), about 1.1% (w/v), or about 1.2% (w/v). The intranasalformulation may comprise more than about 0.1% (w/v) isotonicity agent.The intranasal formulation may comprise less than about 1.2% (w/v)isotonicity agent. In other embodiments, the intranasal formulation maycomprise between about 0.2% (w/v) and about 1.9% (w/v) isotonicityagent, such as about 0.2% (w/v), about 0.3% (w/v), about 0.4% (w/v),about 0.5% (w/v), about 0.6% (w/v), about 0.7% (w/v), about 0.8% (w/v),about 0.9% (w/v), about 1.0% (w/v), about 1.1% (w/v), about 1.2% (w/v),about 1.3% (w/v), about 1.4% (w/v), about 1.5% (w/v), about 1.6% (w/v),about 1.7% (w/v), about 1.8% (w/v), or about 1.9% (w/v). The intranasalformulation may comprise less than about 1.9% (w/v) isotonicity agent.

In certain embodiments, the formulation additionally comprises anabsorption enhancer. In certain embodiments, the pharmaceuticalformulation comprises between about 0.005% (w/v) to about 2.5% (w/v) ofthe absorption enhancer. In certain embodiments, the pharmaceuticalformulation comprises between about 0.05% (w/v) to about 2.5% (w/v) ofthe absorption enhancer. In certain embodiments, the pharmaceuticalformulation comprises between about 0.1% (w/v) to about 0.5% (w/v) ofthe absorption enhancer. In certain embodiments, the pharmaceuticalformulation comprises about 0.25% (w/v) of the absorption enhancer. Incertain embodiments, the pharmaceutical formulation comprises about0.18% (w/v) of the absorption enhancer.

In certain embodiments, the absorption enhancer is selected frombenzalkonium chloride, cyclodextrins, chitosan, deoxycholic acid, analkylsaccharide (e.g., a nonionic alkylsaccharide surfactant such as analkylglycoside and a sucrose ester of fatty acids that consists of analiphatic hydrocarbon chain coupled to a sugar moiety by a glycosidic orester bond, respectively), fusidic acid derivatives, glycocholic acid,laureth-9, phosphatidylcholines, taurocholic acid, taurodihydrofusidicacid, microspheres and liposomes, and bile salts. In certainembodiments, the absorption enhancer is benzalkonium chloride. Theformulation may comprise about 0.01% (w/v) to about 1% (w/v)benzalkonium chloride. In certain embodiments, the pharmaceuticalformulation comprises about 0.005% (w/v) to about 0.015% (w/v)benzalkonium chloride. In certain embodiments, the pharmaceuticalformulation comprises about 0.01% (w/v), about 0.02% (w/v), about 0.03%(w/v), or about 0.04% (w/v) of benzalkonium chloride. In certainembodiments, the pharmaceutical formulation comprises about 0.01% (w/v)benzalkonium chloride. In certain embodiments, the pharmaceuticalformulation comprises about 0.02% (w/v) benzalkonium chloride. Incertain embodiments, the pharmaceutical formulation comprises about0.04% benzalkonium chloride.

In certain embodiments, the pharmaceutical formulation comprisesbenzalkonium chloride in an amount between about 0.001% (w/v) and about1% (w/v). In certain other embodiments, the pharmaceutical formulationcomprises benzalkonium chloride in an amount between about 0.001% (w/v)and about 0.5% (w/v). In certain other embodiments, the pharmaceuticalformulation comprises benzalkonium chloride in an amount between about0.001% (w/v) and about 0.2% (w/v). In some embodiments, thepharmaceutical formulation comprises 0.001% (w/v), 0.003% (w/v), 0.005%(w/v), 0.007% (w/v), 0.009% (w/v), 0.01% (w/v), 0.02% (w/v), 0.03%(w/v), 0.04% (w/v), 0.05% (w/v), 0.06% (w/v), 0.07% (w/v), 0.08% (w/v),0.09% (w/v), 0.1% (w/v), 0.11% (w/v), 0.12% (w/v), 0.13% (w/v), 0.14%(w/v), 0.15% (w/v), 0.16% (w/v), 0.17% (w/v), 0.18% (w/v), 0.19% (w/v),0.2% (w/v), 0.31% (w/v), 0.22% (w/v), 0.23% (w/v), 0.24% (w/v), 0.25%(w/v), 0.26% (w/v), 0.27% (w/v), 0.28% (w/v), 0.29% (w/v), 0.3% (w/v),0.31% (w/v), 0.32% (w/v), 0.33% (w/v), 0.34% (w/v), 0.35% (w/v), 0.36%(w/v), 0.37% (w/v), 0.38% (w/v), 0.39% (w/v), 0.4% (w/v), 0.41% (w/v),0.42% (w/v), 0.43% (w/v), 0.44% (w/v), 0.45% (w/v), 0.46% (w/v), 0.47%(w/v), 0.48% (w/v), 0.49% (w/v), 0.5% (w/v), 0.51% (w/v), 0.52% (w/v),0.53% (w/v), 0.54% (w/v), 0.55% (w/v), 0.56% (w/v), 0.57% (w/v), 0.58%(w/v), 0.59% (w/v), 0.6% (w/v), 0.61% (w/v), 0.62% (w/v), 0.63% (w/v),0.64% (w/v), 0.65% (w/v), 0.66% (w/v), 0.67% (w/v), 0.68% (w/v), 0.69%(w/v), 0.7% (w/v), 0.71% (w/v), 0.72% (w/v), 0.73% (w/v), 0.74% (w/v),0.75% (w/v), 0.76% (w/v), 0.77% (w/v), 0.78% (w/v), 0.79% (w/v), 0.8%(w/v), 0.81% (w/v), 0.82% (w/v), 0.83% (w/v), 0.84% (w/v), 0.85% (w/v),0.86% (w/v), 0.87% (w/v), 0.88% (w/v), 0.89% (w/v), 0.9% (w/v), 0.91%(w/v), 0.92% (w/v), 0.93% (w/v), 0.94% (w/v), 0.95% (w/v), 0.96% (w/v),0.97% (w/v), 0.98% (w/v), 0.99% (w/v), or 1% (w/v) benzalkoniumchloride.

In certain embodiments, the absorption enhancer is an alkylsaccharide.In certain embodiments, the alkylsaccharide is chosen from dodecylmaltoside, tetradecyl maltoside (TDM) and sucrose dodecanoate.

In certain embodiments, the alkylsaccharide is dodecyl maltoside (thealkylglycoside 1-O-n-dodecyl-β-D-maltopyranoside, alternately referredto as lauryl-β-D-maltopyranoside, dodecyl maltopyranoside, and DDM;C₂₄H₄₆Q₁₁, often referred to by the trade name Intravail®).Alkylsaccharides are used in commercial food and personal care productsand have been designated Generally Recognized as Safe (GRAS) substancesfor food applications. They are non-irritating enhancers of transmucosalabsorption that are odorless, tasteless, non-toxic, non-mutagenic, andnon-sensitizing in the Draize test up to a 25% concentration.Alkylsaccharides increase absorption by increasing paracellularpermeability, as indicated by a decrease in transepithelial electricalresistance; they may also increase transcytosis. The effect isshort-lived. Other alkylsaccharides include tetradecyl maltoside (TDM)and sucrose dodecanoate.

In certain embodiments, an intranasal formulation comprises betweenabout 0.05% (w/v) and about 2.5% (w/v) Intravail®. In certainembodiments, an intranasal formulation comprises between about 0.1%(w/v) and about 0.5% (w/v) Intravail®. In certain embodiments, anintranasal formulation comprises between about 0.15% (w/v) and about0.35% (w/v) Intravail®. In certain embodiments, an intranasalformulation comprises between about 0.15% (w/v) and about 0.2% (w/v)Intravail®. In certain embodiments, an intranasal formulation comprisesabout 0.18% (w/v) Intravail®. In certain embodiments, an intranasalformulation comprises about 0.2% (w/v) to about 0.3% (w/v) Intravail®.In certain embodiments, an intranasal formulation comprises about 0.25%(w/v) Intravail®.

In certain embodiments, the absorption enhancer is Intravail® (dodecylmaltoside).

In certain embodiments, the absorption enhancer in the intranasalformulation is a combination of dodecyl maltoside and benzalkoniumchloride. While the use of dodecyl maltoside or benzalkonium chloride asan absorption enhancer in the intranasal formulations described hereinprovides bioavailability of intranasal epinephrine, the combination ofdodecyl maltoside and benzalkonium chloride as absorption enhancers inthe intranasal formulations described herein provides pharmacokineticsthat closely match pharmacokinetics obtained through intramuscularinjection of epinephrine.

In certain embodiments, each dose dispensed from the device of thepharmaceutical formulation comprises between about 0.4 mg and about 2.40mg per dose epinephrine, or a salt thereof, and between 0.1 and 0.50 mgIntravail® (dodecyl maltoside).

In certain embodiments, each dose dispensed from the device of theformulation comprises between about 0.5 mg and about 2.0 mg per doseepinephrine, or a salt thereof, and about between 0.1 and 0.50 mgIntravail® (dodecyl maltoside).

In certain embodiments, each dose dispensed from the device of theformulation comprises between about 0.75 mg and about 1.5 mg per doseepinephrine, or a salt thereof, and between 0.1 and 0.50 mg Intravail®(dodecyl maltoside).

In certain embodiments, each dose dispensed from the device of theformulation comprises between about 0.9 mg and about 1.15 mg per doseepinephrine, or a salt thereof, and about 0.25 mg Intravail® (dodecylmaltoside).

In certain embodiments, each dose dispensed from the device of theformulation comprises about 1.0 mg per dose epinephrine, or a saltthereof, and about 0.25 mg Intravail® (dodecyl maltoside).

In certain embodiments, the pharmaceutical formulation additionallycomprises a chelating agent or antioxidant (stabilizing agent) toimprove stability. In certain embodiments, the chelating/stabilizingagent is EDTA.

Examples of additional stabilizing agents include: acacia, agar,albumin, alginic acid, aluminum stearate, ammonium alginate, ascorbicacid, ascorbyl palmitate, bentonite, butylated hydroxytoluene (BHT),calcium alginate, calcium stearate, carboxymethylcellulose calcium,carboxymethylcellulose sodium, carrageenan, cellulose, microcrystalline,carboxymethylcellulose sodium, ceratonia, colloidal silicon dioxide,cyclodextrins, diethanolamine, edetates, ethylcellulose, ethylene glycolpalmitostearate, glycerin monostearate, guar gum, hectorite,hydroxpropyl betadex, hydroxypropyl cellulose, hypromellose, inulin,invert sugar, lauric acid, lecithin, magnesium aluminum silicate,mineral oil and lanolin alcohols, monoethanolamine, pectin, penteticacid, phospholipids, polacrilin potassium, poloxamer, polyvinyl alcohol,potassium alginate, potassium chloride, povidone, propyl gallate,propylene glycol, propylene glycol alginate, raffinose, sodium acetate,sodium alginate, sodium borate, sodium stearyl fumarate, sorbitol,stearyl alcohol, sulfobutylether b-cyclodextrin, tagatose, trehalose,triethanolamine, white wax, xanthan gum, xylitol, yellow wax, and zincacetate.

Examples of additional chelating agents include: citric acidmonohydrate, disodium edetate, edetate calcium disodium, edetic acid,fumaric acid, malic acid, maltol, pentetic acid, sodium edetate, andtrisodium edetate.

In certain embodiments, the pharmaceutical formulation comprisesbenzalkonium chloride. In certain embodiments, the pharmaceuticalformulation comprises about 0.005% (w/v) to about 1% (w/v) benzalkoniumchloride.

In its capacity as a surfactant, benzalkonium chloride can affect thesurface tension of droplets from a delivered nasal spray plume,producing spherical or substantially spherical particles having a narrowdroplet size distribution (DSD), as well as the viscosity of a liquidformulation.

In certain embodiments, the absorption enhancer is an alkylsaccharide,for example, a nonionic alkylsaccharide surfactant such as analkylglycoside and a sucrose ester of fatty acids that consists of analiphatic hydrocarbon chain coupled to a sugar moiety by a glycosidic orester bond, respectively. In certain embodiments, the absorptionenhancer is an alkylmaltoside (e.g., a tetradecyl maltoside (TDM), adodecyl maltoside (DDM), etc.). In certain embodiments, the absorptionenhancer is sucrose dodecanoate. Alkylsaccharides are used in commercialfood and personal care products and have been designated GenerallyRecognized as Safe (GRAS) substances for food applications. They arenon-irritating enhancers of transmucosal absorption that are odorless,tasteless, non-toxic, non-mutagenic, and non-sensitizing in the Draizetest up to a 25% concentration. Without being bound to any theory, it isbelieved that alkylsaccharides increase absorption by increasingparacellular permeability, as indicated by a decrease in transepithelialelectrical resistance; they may also increase transcytosis. The effectmay be short-lived. In its capacity as an absorption enhancer,alkylmaltosides (e.g., a tetradecyl maltoside (TDM), a dodecyl maltoside(DDM), etc.) can affect the surface tension of droplets from a deliverednasal spray plume, producing spherical or substantially sphericalparticles having a narrow droplet size distribution (DSD), as well asthe viscosity of a liquid formulation.

In certain embodiments, the absorption enhancer is the alkylsaccharide1-O-n-dodecyl-β-D-maltopyranoside (alternately referred to aslauryl-β-D-maltopyranoside, dodecyl maltopyranoside, dodecyl maltoside,and DDM; C₂₄H₄₆Q₁₁; often referred to by the trade name Intravail®). Incertain embodiments, an intranasal formulation comprises about 0.01%(w/v) to about 2.5% (w/v) DDM. In certain embodiments, an intranasalformulation comprises about 0.1% (w/v) to about 0.5% (w/v) DDM. Incertain embodiments, an intranasal formulation comprises about 0.15%(w/v) to about 0.35% (w/v) DDM. In certain embodiments, an intranasalformulation comprises about 0.15% (w/v) to about 0.2% (w/v) DDM. Incertain embodiments, an intranasal formulation comprises about 0.18%(w/v) DDM. In certain embodiments, an intranasal formulation comprisesabout 0.2% (w/v) to about 0.3% (w/v) DDM. In certain embodiments, anintranasal formulation comprises about 0.25% (w/v) DDM.

In sugar chemistry, an anomer is either of a pair of cyclicstereoisomers (designated α or β) of a sugar or glycoside, differingonly in configuration at the hemiacetal (or hemiketal) carbon, alsocalled the anomeric carbon or reducing carbon. If the structure isanalogous to one with the hydroxyl group on the anomeric carbon in theaxial position of glucose, then the sugar is an alpha anomer. If,however, that hydroxyl is equatorial, the sugar is a beta anomer. Forexample, α-D-glucopyranose and β-D-glucopyranose, the two cyclic formsof glucose, are anomers. Likewise, alkylglycosides occur as anomers. Forexample, dodecyl β-D-maltoside and dodecyl α-D-maltoside are two cyclicforms of dodecyl maltoside. The two different anomers are two distinctchemical structures, and thus have different physical and chemicalproperties. In one aspect of the invention, the alkylglycoside of thepresent invention is a β anomer. In an exemplary aspect, thealkylglycoside is a β anomer of an alkylmaltoside, such astetradecyl-β-D-maltoside (TDM).

In some embodiments, the alkylglycoside used is a substantially purealkylglycoside. As used herein a “substantially pure” alkylglycosiderefers to one anomeric form of the alkylglycoside (either the a or βanomeric forms) with less than about 2% of the other anomeric form,preferably less than about 1.5% of the other anomeric form, and morepreferably less than about 1% of the other anomeric form. In one aspect,a substantially pure alkylgycoside contains greater than 98% of eitherthe a or β anomer. In another aspect, a substantially pure alkylgycosidecontains greater than 99% of either the a or β anomer. In anotheraspect, a substantially pure alkylgycoside contains greater than 99.5%of either the a or β anomer. In another aspect, a substantially purealkylgycoside contains greater than 99.9% of either the a or β anomer.

In certain embodiments, described herein is an aqueous formulationsuitable for intranasal administration comprising: epinephrine; water;and one or more ingredients selected from absorption enhancers,chelating agents, antioxidants, stabilizing agents, surfactants,isotonicity agents, and pH adjusting agents.

In certain embodiments, described herein is an aqueous formulationsuitable for intranasal administration comprising: epinephrine; water;and one or more ingredients selected from alkylglycosides, chitosan,alkylcyclodextrins, benzalkonium chloride, sodium chloride, and EDTA.

In certain embodiments, described herein is an aqueous formulationsuitable for intranasal administration comprising: epinephrine; water;and one or more ingredients selected from dodecyl maltoside (DDM),tetradecyl maltoside (TDM), benzalkonium chloride, sodium chloride,hydrochloric acid, and EDTA. In certain other embodiments, describedherein is an aqueous formulation suitable for intranasal administrationcomprising: epinephrine; water; and one or more ingredients selectedfrom dodecyl maltoside (DDM), benzalkonium chloride, sodium chloride,and EDTA.

In certain embodiments, described herein is an aqueous formulationsuitable for intranasal administration comprising: epinephrine; water;dodecyl maltoside (DDM); and one or more ingredients selected frombenzalkonium chloride, sodium chloride, pH adjusting agents, and EDTA.

In certain embodiments, described herein is an aqueous formulationsuitable for intranasal administration comprising: epinephrine; water;benzalkonium chloride; and one or more ingredients selected from dodecylmaltoside (DDM), sodium chloride, pH adjusting agents, and EDTA.

In certain embodiments, described herein is an aqueous formulationsuitable for intranasal administration comprising: epinephrine; water;dodecyl maltoside (DDM) or benzalkonium chloride or a combination ofdodecyl maltoside (DDM) and benzalkonium chloride; and one or moreadditional ingredients selected from sodium chloride, pH adjustingagents, and EDTA.

pH adjusting agents include acids described herein (e.g. hydrochloricacid, citric acid), buffers (e.g. phosphate, acetate, and citratebuffers), and bases (e.g. sodium hydroxide, sodium citrate, sodiumbicarbonate, sodium carbonate).

In certain embodiments, described herein is an aqueous formulationsuitable for intranasal administration comprising: about 0.5% (w/v) toabout 2.5% (w/v) epinephrine; water; and one or more ingredientsselected from: about 0.05% (w/v) to about 2.5% (w/v) dodecyl maltoside(DDM); about 0.005% (w/v) to about 1% (w/v) benzalkonium chloride; about0.2% (w/v) to about 1.2% (w/v) sodium chloride, optional hydrochloricacid or sodium hydroxide in a sufficient amount to adjust the pH to afinal pH of about 4.0 to about 5.0; and about 0.05% (w/v) to about 2.0%(w/v) EDTA.

In certain embodiments, described herein is an aqueous formulationsuitable for intranasal administration comprising: i) about 0.5% (w/v)to about 2.5% (w/v) epinephrine; ii) water; iii) about 0.05% (w/v) toabout 2.5% (w/v) dodecyl maltoside (DDM) or about 0.005% (w/v) to about1% (w/v) benzalkonium chloride, or a combination of about 0.05% (w/v) toabout 2.5% (w/v) dodecyl maltoside (DDM) and about 0.005% (w/v) to about1% (w/v) benzalkonium chloride; and iv) one or more ingredients selectedfrom a) about 0.2% (w/v) to about 1.2% (w/v) sodium chloride; b)optional hydrochloric acid or sodium hydroxide in an amount sufficientto adjust the pH to a final pH of about 4.0 to about 5.0; and c) about0.05% (w/v) to about 2.0% (w/v) EDTA.

In certain embodiments, described herein is an aqueous formulationsuitable for intranasal administration comprising: i) about 0.9% (w/v)to about 2.0% (w/v) epinephrine; ii) water; iii) about 0.05% (w/v) toabout 2.5% (w/v) dodecyl maltoside (DDM), or about 0.005% (w/v) to about1% (w/v) benzalkonium chloride, or a combination of about 0.05% (w/v) toabout 2.5% (w/v) dodecyl maltoside (DDM) and about 0.005% (w/v) to about1% (w/v) benzalkonium chloride; and iv) one or more ingredients selectedfrom a) about 0.2% (w/v) to about 1.2% (w/v) sodium chloride; b)optional hydrochloric acid or sodium hydroxide hydrochloric acid in anamount sufficient to adjust the pH to a final pH of about 4.0 to about5.0; and c) about 0.05% (w/v) to about 2.0% (w/v) EDTA.

In certain embodiments, described herein is an aqueous formulationsuitable for intranasal administration comprising: about 0.5% (w/v) toabout 2.5% (w/v) epinephrine; water; about 0.05% (w/v) to about 2.5%(w/v) dodecyl maltoside (DDM); about 0.005% (w/v) to about 1% (w/v)benzalkonium chloride; about 0.2% (w/v) to about 1.2% (w/v) sodiumchloride, hydrochloric acid in a sufficient amount to adjust the pH to afinal pH of about 4.0 to about 5.0; and about 0.05% (w/v) to about 2.0%(w/v) EDTA.

In certain embodiments, described herein is an aqueous formulationsuitable for intranasal administration comprising: epinephrine; water;one or more absorption enhancement agents; an isotonicity agent; astabilizing agent; a preservative; and optional pH adjustment agents toadjust pH to pH 3 to 6. In certain embodiments, described herein is anaqueous formulation suitable for intranasal administration comprising:epinephrine; water; one or more absorption enhancement agents (e.g.dodecyl maltoside; benzalkonium chloride; or a combination of dodecylmaltoside and benzalkonium chloride); an isotonicity agent (e.g. sodiumchloride); a stabilizing agent (e.g. EDTA or disodium EDTA); apreservative (e.g. benzalkonium chloride); and optional pH adjustmentagents to adjust pH to pH 3 to 6. In certain embodiments, describedherein is an aqueous formulation suitable for intranasal administrationcomprising: epinephrine; water; one or more absorption enhancementagents (e.g. dodecyl maltoside; benzalkonium chloride; or a combinationof dodecyl maltoside and benzalkonium chloride); an isotonicity agent(e.g. sodium chloride); a stabilizing agent (e.g. EDTA or disodiumEDTA); a preservative (e.g. benzalkonium chloride); an antioxidant; abuffering agent; and optional pH adjustment agents to adjust pH to pH 3to 6.

In certain embodiments, described herein is an aqueous formulationsuitable for intranasal administration comprising: epinephrine; water;dodecyl maltoside or benzalkonium chloride or a combination of dodecylmaltoside and benzalkonium chloride; sodium chloride; EDTA or disodiumEDTA; and optional pH adjustment agents to adjust pH to pH 3 to 6.

In certain embodiments, described herein is an aqueous formulationsuitable for intranasal administration comprising: about 0.5% (w/v) toabout 2.5% (w/v) epinephrine; water; about 0.05% (w/v) to about 2.5%(w/v) dodecyl maltoside or about 0.005% (w/v) to about 1% (w/v)benzalkonium chloride or a combination of about 0.05% (w/v) to about2.5% (w/v) dodecyl maltoside and about 0.005% (w/v) to about 1% (w/v)benzalkonium chloride; about 0.2% (w/v) to about 1.2% (w/v) sodiumchloride; about 0.05% (w/v) to about 2.0% (w/v) EDTA or disodium EDTA;and optional pH adjustment agents to adjust pH to pH 3 to 6.

In some embodiments, a 100 μL sample of the aqueous formulation suitablefor intranasal administration comprises less than about 2.5 mg ofepinephrine. In some embodiments, a 100 μL sample of the aqueousformulation suitable for intranasal administration comprises about 0.5mg to about 2.5 mg of epinephrine. In some embodiments, a 100 μL sampleof the aqueous formulation suitable for intranasal administrationcomprises about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about2.4 mg, or about 2.5 mg of epinephrine.

Nasal Drug Delivery Devices and Kits

Also provided are nasal drug delivery devices comprising a formulationdescribed herein. In certain embodiments, the device is pre-primed. Incertain embodiments, the device can be primed before use. In certainembodiments, the device can be actuated with one hand.

Nasal delivery is considered an attractive, safe, and easy-to-administerroute for needle-free, systemic drug delivery, especially when rapidabsorption and effect are desired. In addition, nasal delivery may helpaddress issues related to poor bioavailability, slow absorption, drugdegradation, and adverse events (AEs) in the gastrointestinal tract andavoids the first-pass metabolism in the liver.

Liquid nasal formulations are mainly aqueous solutions, but suspensions,emulsions, liposomes, and microspheres can also be delivered. Otherliquid formulations can comprise liposomes, microspheres, mixedaqueous-organic formulations, non-aqueous formulations, dry powder andretentive formulations (gels). In traditional spray pump systems,antimicrobial preservatives are typically required to maintainmicrobiological stability in liquid formulations. Metered spray pumpshave dominated the nasal drug delivery market since they wereintroduced. The pumps typically deliver 100 μL (25-250 μL) per spray,and they offer high reproducibility of the emitted dose and plumegeometry in in vitro tests.

Examples of standard metered spray pumps include those offered by AptarPharma, Inc., such as the multi-dose “classic technology platform” nasalspray devices, and by BD Medical-Pharmaceutical Systems, such as theAccuspray™ system. Such devices comprise a reservoir which holdsmultiple doses of the nasal spray formulation (e.g., 50, 100, 150, 200,60, or 120 doses), a closure (e.g., screw, crimp, or snap-on), and anactuator which delivers anywhere from 45 to 1000 μL (e.g. 50, 100, 140,150, or 200 μL) of fluid per actuation to comprise a single dose. Theactuator may be configured to count doses, deliver gel formulations,deliver in an upside-down configuration, etc.

In traditional multi-use spray pump systems, antimicrobial preservativesare typically required to maintain microbiological stability in liquidformulations. However, preservative-free systems are also available,e.g. the Advanced Preservative Free (APF) system from Aptar, which isvented, contains a filter membrane for air flow which preventscontamination, has a metal-free fluid path for oxidizing formulations,and can be used in any orientation. Additional nasal spray devices fromAptar and others are optimized with dispenser tips that prevent clogging(useful for high-viscosity and high-volatile formulations), actuatorsthat do not need re-priming after long periods of disuse, etc.Additional nasal spray devices are propellant driven. Yet additionalnasal spray devices include dry powder inhalers.

The particle size and plume geometry can vary within certain limits anddepend on the properties of the pump, the formulation, the orifice ofthe actuator, and the force applied. The droplet size distribution of anasal spray is a critical parameter, since it significantly influencesthe in vivo deposition of the drug in the nasal cavity. The droplet sizeis influenced by the actuation parameters of the device and theformulation. The prevalent median droplet size should be between about30 and about 100 μm. If the droplets are too large (>about 120 μm),deposition takes place mainly in the anterior parts of the nose, and ifthe droplets are too small (<about 10 μm), they can possibly be inhaledand reach the lungs and oral cavity, which should be avoided because ofsafety reasons. In its capacity as a surfactant, benzalkonium chlorideand alkylmaltosides (e.g., a tetradecyl maltoside (TDM), a dodecylmaltoside (DDM), etc.) can affect the surface tension of droplets from adelivered nasal spray plume, producing spherical or substantiallyspherical particles having a narrow droplet size distribution (DSD), aswell as the viscosity of a liquid formulation.

Plume geometry, droplet size and DSD of the delivered plume subsequentto spraying may be measured under specified experimental andinstrumental conditions by appropriate and validated and/or calibratedanalytical procedures known in the art. These include photography, laserdiffraction, and impaction systems (cascade impaction, NGI). Plumegeometry, droplet size and DSD can affect pharmacokinetic outcomes suchas C_(max), T_(max), and dose proportionality. Droplet size distributioncan be controlled in terms of ranges for the D10, D50, D90, span[(D90−D10)/D50], and percentage of droplets less than 10 mm. In certainembodiments, the formulation will have a narrow DSD. In certainembodiments, the formulation will have a D(v,50) of 30-70 μm and a D(v,90)<100 μm.

In certain embodiments, the percent of droplets less than 10 μm will beless than 10%. In certain embodiments, the percent of droplets less than10 μm will be less than 5%. In certain embodiments, the percent ofdroplets less than 10 μm will be less than 2%. In certain embodiments,the percent of droplets less than 10 μm will be less than 1%.

In certain embodiments, the formulation when dispensed by actuation fromthe device will produce a uniform circular plume with an ovality ratioclose to 1. Ovality ratio is calculated as the quotient of the maximumdiameter (D_(max)) and the minimum diameter (D_(min)) of a spray patterntaken orthogonal to the direction of spray flow (e.g., from the “top”).In certain embodiments, the ovality ratio is less than ±2.0. In certainembodiments, the ovality ratio is less than ±1.5. In certainembodiments, the ovality ratio is less than ±1.3. In certainembodiments, the ovality ratio is less than ±1.2. In certainembodiments, the ovality ratio is less than ±1.1.

The details and mechanical principles of particle generation fordifferent types of nasal aerosol devices has been described. See,Vidgren and Kublik, Adv. Drug Deliv. Rev. 29:157-77, 1998. Traditionalspray pumps replace the emitted liquid with air, and preservatives aretherefore required to prevent contamination. However, driven by thestudies suggesting possible negative effects of preservatives, pumpmanufacturers have developed different spray systems that avoid the needfor preservatives. These systems use a collapsible bag, a movablepiston, or a compressed gas to compensate for the emitted liquid volume(on the World Wide Web at aptar.com and on the World Wide Web atrexam.com). The solutions with a collapsible bag and a movable pistoncompensating for the emitted liquid volume offer the additionaladvantage that they can be emitted upside down, without the risk ofsucking air into the dip tube and compromising the subsequent spray.This may be useful for some products where the patients are bedriddenand where a head-down application is recommended. Another method usedfor avoiding preservatives is that the air that replaces the emittedliquid is filtered through an aseptic air filter. In addition, somesystems have a ball valve at the tip to prevent contamination of theliquid inside the applicator tip. More recently, pumps have beendesigned with side-actuation. The pump was designed with a shorter tipto avoid contact with the sensitive mucosal surfaces. New designs toreduce the need for priming and re-priming, and pumps incorporatingpressure point features to improve the dose reproducibility and dosecounters and lock-out mechanisms for enhanced dose control and safetyare available (on the World Wide Web at rexam.com and on the World WideWeb at aptar.com).

Traditional, simple single, bi-dose and multi-use metered-dose spraypumps require priming and some degree of overfill to maintain doseconformity for the labeled number of doses. They are well suited fordrugs to be administered daily over a prolonged duration, but due to thepriming procedure and limited control of dosing, unless a specialtydevice is selected, they are less suited for drugs with a narrowtherapeutic window of time in which to use the device, particularly ifthey are not used often. For expensive drugs and drugs intended forsingle administration or sporadic use and where tight control of thedose and formulation is of importance, single-dose (UDS) or bi-dosespray (BDS) devices are preferred (on the World Wide Web at aptar.com).A simple variant of a single-dose spray device (MAD™) is offered by LMA(LMA, Salt Lake City, UT, USA; on the World Wide Web at lmana. com). Anosepiece with a spray tip is fitted to a standard syringe. The liquiddrug to be delivered is first drawn into the syringe and then the spraytip is fitted onto the syringe. This device has been used in academicstudies to deliver, for example, a topical steroid in patients withchronic rhinosinusitis and in a vaccine study. A pre-filled device basedon the same principle for one or two doses (Accuspray™, Becton DickinsonTechnologies, Research Triangle Park, NC, USA; on the World Wide Web atbdpharma.com) is used to deliver the influenza vaccine FluMist™ (on theWorld Wide Web at flumist.com), approved for both adults and children inthe US market. A similar device for two doses was marketed by a Swisscompany for delivery of another influenza vaccine a decade ago.

Pre-primed single- and bi-dose devices are also available, and consistof a reservoir, a piston, and a swirl chamber (see, e.g., the UDSUnitDose™ and BDS BiDose™ devices from Aptar, formerly Pfeiffer). Thespray is formed when the liquid is forced out through the swirl chamber.These devices are held between the second and the third fingers with thethumb on the actuator. A pressure point mechanism incorporated in somedevices secures reproducibility of the actuation force and emitted plumecharacteristics. Currently, marketed nasal migraine drugs like Imitrex®(on the World Wide Web at gsk.com) and Zomig® (on the World Wide Web ataz.com; Pfeiffer/Aptar single-dose device), the marketed influenzavaccine Flu-Mist (on the World Wide Web at flumist.com; Becton Dickinsonsingle-dose spray device), and the intranasal formulation of naloxonefor opioid overdose rescue, Narcan Nasal® (on the World Wide Web atnarcan.com; Adapt Pharma) are delivered with this type of device.

In certain embodiments, the 90% confidence interval for dose deliveredper actuation is ±about 2%. In certain embodiments, the 95% confidenceinterval for dose delivered per actuation is ±about 2.5%.

Historically, intranasal administration of drugs in large volume, suchas from syringes adapted with mucosal atomizer devices (MADs), hasencountered difficulty due to the tendency of some of the formulation todrip back out of the nostril or down the nasopharynx. Accordingly, incertain embodiments, upon nasal delivery of said pharmaceuticalformulation to said patient, less than about 20% of said pharmaceuticalformulation leaves the nasal cavity via drainage into the nasopharynx orexternally. In certain embodiments, upon nasal delivery of saidpharmaceutical formulation to said patient, less than about 10% of saidpharmaceutical formulation leaves the nasal cavity via drainage into thenasopharynx or externally. In certain embodiments, upon nasal deliveryof said pharmaceutical formulation to said patient, less than about 5%of said pharmaceutical formulation leaves the nasal cavity via drainageinto the nasopharynx or externally.

Current container closure system designs for inhalation spray drugproducts include both pre-metered and device-metered presentations usingmechanical or power assistance and/or energy from patient inspirationfor production of the spray plume. Pre-metered presentations containpreviously measured doses or a dose fraction in some type of units(e.g., single or multiple blisters or other cavities) that aresubsequently inserted into the device during manufacture or by thepatient before use. Typical device-metered units have a reservoircontaining formulation sufficient for multiple doses that are deliveredas metered sprays by the device itself when activated by the patient.

With aseptic techniques, the use of preservatives may not be required inpre-primed devices, but overfill is required resulting in a wastefraction similar to the metered-dose, multi-dose sprays. To emit 100 μL,a volume of 125 μL is filled in the device (Pfeiffer/Aptar single-dosedevice) used for the intranasal migraine medications Imitrex™(sumatriptan) and Zomig™ (zolmitriptan) and about half of that for abi-dose design. Sterile drug products may be produced using asepticprocessing or terminal sterilization. Terminal sterilization usuallyinvolves filling and sealing product containers under high-qualityenvironmental conditions. Products are filled and sealed in this type ofenvironment to minimize the microbial and particulate content of thein-process product and to help ensure that the subsequent sterilizationprocess is successful. In most cases, the product, container, andclosure have low bioburden, but they are not sterile. The product in itsfinal container is then subjected to a sterilization process such asheat, irradiation, or chemical (gas). In an aseptic process, the drugproduct, container, and closure are first subjected to sterilizationmethods separately, as appropriate, and then brought together. Becausethere is no process to sterilize the product in its final container, itis critical that containers be filled and sealed in an efficient qualityenvironment. Aseptic processing involves more variables than terminalsterilization. Before aseptic assembly into a final product, theindividual parts of the final product generally can be subjected tovarious sterilization processes. For example, glass containers aresubjected to dry heat; rubber closures are subjected to moist heat; andliquid dosage forms are subjected to filtration. Each of thesemanufacturing processes requires validation and control.

Devices recited herein may employ any of the pharmaceuticalformulations, and are useful in the methods disclosed herein.

Accordingly, provided herein are devices adapted for nasal delivery of apharmaceutical formulation to a patient, comprising a reservoir with atherapeutically effective amount of epinephrine.

In certain embodiments, epinephrine is the only pharmaceutically activecompound in the pharmaceutical formulation.

In certain embodiments, the volume of the pharmaceutical formulation inthe reservoir is not more than about 140 μL.

In certain embodiments, the volume of the pharmaceutical formulation inthe reservoir is above about 125 μL and less than 140 μL.

In certain embodiments, about 100 μl of the pharmaceutical formulationin the reservoir is delivered to the patient in one actuation.

In some embodiments, about 100 μl of the pharmaceutical formulation inthe reservoir is delivered to the patient in one actuation and comprisesless than about 2.5 mg of epinephrine. In some embodiments, about 100 μLof the pharmaceutical formulation in the reservoir is delivered to thepatient in one actuation and comprises about 0.5 mg to about 2.5 mg ofepinephrine. In some embodiments, about 100 μL of the pharmaceuticalformulation in the reservoir is delivered to the patient in oneactuation and comprises about 0.5 mg, about 0.6 mg, about 0.7 mg, about0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about2.3 mg, about 2.4 mg, or about 2.5 mg of epinephrine.

In certain embodiments, the pharmaceutical formulation further comprisesone or more excipients selected from water, EDTA, and sodium chloride.In certain embodiments, the pharmaceutical formulation further comprisesbenzalkonium chloride.

In some embodiments, about 100 μL of the aqueous pharmaceuticalformulation in the reservoir is delivered to the patient in oneactuation and comprises epinephrine, dodecylmaltoside or benzalkoniumchloride or a combination of dodecylmaltoside and benzalkonium chloride,EDTA, and NaCl.

In certain embodiments, the pharmaceutical formulation is substantiallyfree of antimicrobial preservatives.

In certain embodiments, the pharmaceutical formulation further comprisesa compound which acts as a preservative, absorption enhancer and/or acationic surfactant; an isotonicity agent; a stabilizing agent; and anamount of acid or base sufficient to achieve a pH of about 3.5 to about6.0. The use of absorption enhancers, such as alkylsaccharides,cyclodextrins, and chitosans may increase the rate at which epinephrineis absorbed. In general, absorption enhancers provide improvedpharmacokinetic outcomes such as increased C_(max), reduced T_(max), anddose proportionality compared to both intramuscular formulations andintranasal formulations that do not contain an absorption enhancer.Without being bound to any theory, such absorption enhancers typicallyoperate by affecting two primary mechanisms for nasal absorption:paracellular transport via opening of tight junctions between cells, andtranscellular transport or transcytosis through cells via vesiclecarriers.

Some absorption enhancing excipients can alter the paracellular and/ortranscellular pathways, others can extend residence time in the nasalcavity or prevent metabolic changes. Without an absorption enhancer, themolecular-weight limit for nasal absorption is about 1 kDa, whileadministration of drugs in conjunction with absorption enhancers canenable the absorption of molecules from 1-30 kDa. Intranasaladministration of most absorption enhancers, however, can cause nasalmucosa damage. Maggio, J. Excipients and Food Chem. 5(2):100-12, 2014.Examples of absorption enhancers include aprotinin, benzalkoniumchloride, benzyl alcohol, capric acid, ceramides, cetylpyridiniumchloride, chitosan, cyclodextrins, deoxycholic acid, decanoyl carnitine,EDTA, glycocholic acid, glycodeoxycholic acid, glycofurol, glycosylatedsphingosines, glycyrrhetinic acids, 2-hydroxypropyl-β-cyclodextrin,laureth-9, lauric acid, lauroyl carnitine, lauryl sulfate,lysophosphatidylcholine, menthol, poloxamer 407, poloxamer F68,poly-L-arginine, polyoxyethylene-9-lauryl ether, polysorbate 80,propylene glycol, quillaia saponin, salicylic acid,β-sitosterol-β-D-glucoside, sucrose cocoate, taurocholic acid,taurodeoxycholic acid, taurodihydrofusidic acid, and alkylsaccharides,such as dodecyl maltoside, tetradecyl maltoside and sucrose dodecanoate.

Epinephrine may optionally exist as pharmaceutically acceptable saltsincluding pharmaceutically acceptable acid addition salts prepared frompharmaceutically acceptable non-toxic acids including inorganic andorganic acids. Representative acids include, but are not limited to,acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic,hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic andthe like. The acid addition salts may be obtained as the direct productsof compound synthesis. In the alternative, the free base may bedissolved in a suitable solvent containing the appropriate acid and thesalt isolated by evaporating the solvent or otherwise separating thesalt and solvent. The salt may form solvates with standard low molecularweight solvents using methods known to the skilled artisan.

In certain embodiments, the device is filled with the pharmaceuticalformulation using sterile filling.

In certain embodiments, the pharmaceutical formulation is chemicallystorage-stable for about twelve months at about 25° C. and about 60%relative humidity and about six months at about 40° C. and about 75%relative humidity.

In some embodiments, intranasal epinephrine is delivered as an aqueoussolution, aqueous suspension, aqueous emulsion, non-aqueous solution,non-aqueous suspensions, non-aqueous emulsion, a solution withhalogenated hydrocarbon propellant(s), or as a dry powder. In someembodiments, aqueous formulations are sprayed into the nostril. In someembodiments, aqueous formulations are aerosolized by liquid nebulizersemploying either hydraulic or ultrasonic atomization. Propellant-basedsystems may use suitable pressurized metered-dose inhalers (pMDIs). Drypowders may use dry powder inhaler devices (DPIs), which are capable ofdispersing the drug substance effectively.

Propellants typically used include chlorofluorocarbons,hydrochlorofluorocarbons, hydrofluorocarbons, hydrocarbons, andcompressed gases.

In some embodiments, intranasal epinephrine is delivered as a nasalaerosol produced by a nasal pressurized metered-dose inhalers (pMDIs).In some embodiments, the pMDI is a hydrofluoroalkane (HFA)-based pMDIfor nasal use. Like spray pumps, nasal pMDIs produce a localizeddeposition on the anterior non-ciliated epithelium of the nasalvestibule and in the anterior parts of the narrow nasal valve, but dueto quick evaporation of the spray delivered with a pMDI, noticeable“drip-out” may be less of an issue.

In some embodiments, epinephrine is delivered with a nebulizer.Nebulizers use compressed gasses (air, oxygen, and nitrogen) orultrasonic or mechanical power to break up medical solutions andsuspensions into small aerosol droplets that can be directly inhaledinto the nose. The smaller particles and slow speed of the nebulizedaerosol increase penetration to the target sites in the middle andsuperior meatuses and the paranasal sinuses.

In some embodiments, epinephrine is delivered with a pulsating aerosolgenerated via a perforated vibrating membrane. In some embodiments, thepulsation membrane nebulizer is VibrENT (PART Pharma GmbH). In someembodiments, epinephrine is delivered with a pulsating aerosol incombination with breathing techniques

In some embodiments, epinephrine is delivered with Bi-Directional™delivery technology (e.g. Bi-Directional™ Exhalation Delivery Systems(EDS); OptiNose).

In some embodiments, epinephrine is delivered with an atomizer. In someembodiments, the atomizer is a handheld battery-driven atomizer intendedfor nasal drug delivery. In some embodiments, the atomizer atomizesliquids by producing a vertical flow on the droplets as they exit thedevice. Such devices include the ViaNase™ atomizer (by Kurve TechnologyInc., Lynnwood, WA, USA). In some embodiments, the atomizer is is anasal atomizer driven by highly pressurized nitrogen gas.

In some embodiments, intranasal epinephrine is delivered with a nasalpowder device. In some embodiments, the nasal powder device is a nasalpowder inhaler, nasal powder sprayer, or nasal powder insufflator.Powder sprayers typically have a compressible compartment to provide apressure that when released creates a plume of powder particles fairlysimilar to that of a liquid spray. Breath-actuated inhalers require theuser to use his or her own breath to inhale the powder into the nostrilfrom a blister or capsule. Nasal insufflator devices consist of amouthpiece and a nosepiece that are fluidly connected. Delivery occurswhen the subject exhales into the mouthpiece to close the velum, and theairflow carries the powder particles into the nose through the devicenosepiece.

In some embodiments, the nasal powder inhaler is a blister based powderinhaler. Typically, the blister is pierced before use and the devicenosepiece placed into one nostril. The subject closes the other nostrilwith the finger and inhales the powder into the nose. Representativedevises include BiDose™/Prohaler™, and Twin-Lizer™.

Representative nasal powder sprayers include, but are not limited to,UnidoseDP™, Fit-Lizer™, Monopowder™, SoluVent™)

In some embodiments, the nasal powder sprayer is a capsule-based,single-dose powder devices. In one such embodiment, the capsule-based,single-dose powder device consist of a chamber that cuts off the top andbottom of the capsule when inserted. A plastic chamber is compressed byhand, compressed air passes through a one-way valve and the capsuleduring actuation, and the powder is emitted.

In some embodiments, the nasal powder sprayer consists of an air-filledcompartment that is compressed until a pin ruptures a membrane torelease pressure that emits a plume of powder.

In some embodiments, the nasal powder sprayer consists of a plunger thatwhen pressed creates a positive pressure that ruptures a membrane toexpel the powder.

In some embodiments, the nasal powder insufflator requires the subjectto blow into one end of the tube while the other end is inserted intothe vestibule of the nostril.

In some embodiments, intranasal epinephrine is delivered with abreath-powered Bi-Directional™delivery device. A breathpoweredBi-Directional™ nasal delivery device utilizes the exhaled breath todeliver the drug into the nose. Breath-powered Bi-Directional™ devicesconsist of a mouthpiece and a sealing nosepiece with an optimizedfrusto-conical shape and comfortable surface that mechanically expandsthe first part of the nasal valve. The user slides a sealing nosepieceinto one nostril until it forms a seal with the flexible soft tissue ofthe nostril opening, at which point, it mechanically expands the narrowslit-shaped part of the nasal triangular valve. The user then exhalesthrough an attached mouthpiece. When exhaling into the mouthpieceagainst the resistance of the device, the soft palate (or velum) isautomatically elevated by the positive oropharyngeal pressure, isolatingthe nasal cavity from the rest of the respiratory system. Owing to thesealing nosepiece, the dynamic pressure that is transferred from themouth through the device to the nose further expands the slit-like nasalpassages. This “breath-powered” mechanism enables release of liquid orpowder particles into an air stream that enters one nostril, passesentirely around the nasal septum, and exits through the oppositenostril. Actuation of drug release in devices employing this approachuse manual triggering or mechanisms automatically triggered by flowand/or pressure.

Single-Dose Devices

In certain embodiments, the device is a single-dose device, wherein thepharmaceutical formulation is present in one reservoir, and wherein thetherapeutically effective amount of the epinephrine is deliveredessentially by one actuation of the device.

Also provided herein is a single-use, pre-primed device adapted fornasal delivery of a pharmaceutical formulation to a patient by oneactuation of the device into one nostril of the patient, having a singlereservoir comprising about 100 μL of a pharmaceutical formulation asdisclosed herein.

In certain embodiments, the device is actuatable with one hand.

In certain embodiments, the delivery time is less than about 30 seconds.In certain embodiments, the delivery time is less than about 25 seconds.In certain embodiments, the delivery time is less than about 20 seconds.In certain embodiments, the delivery time is less than about 15 seconds.

In certain embodiments, the 90% confidence interval for dose deliveredper actuation is ±about 2%. In certain embodiments, the 95% confidenceinterval for dose delivered per actuation is ±about 2.5%.

In certain embodiments, upon nasal delivery of the formulation to thepatient, less than about 20%, less than about 15%, less than about 10%,or less than about 5%, of the formulation leaves the nasal cavity viadrainage into the nasopharynx or externally, as provided above.

In certain embodiments, said formulation is chemically storage-stablefor about twelve months at about 25° C. and about 60% relative humidityand/or about six months at about 40° C. and about 75% relative humidity.

Bi-Dose Devices

In certain embodiments, said device is a bi-dose device, wherein a firstvolume of said formulation is present in a first reservoir and a secondvolume of said formulation is present in a second reservoir, and whereinsaid therapeutically effective amount is delivered essentially by afirst actuation of said device into a first nostril of said patient anda second actuation of said device into a second nostril of said patient.

In certain embodiments, said first volume and said second volumecombined is equal to not more than about 380 μL.

In certain embodiments, about 100 μL of said first volume of saidformulation is delivered by said first actuation.

In certain embodiments, about 100 μL of said second volume of saidformulation is delivered by said second actuation.

In certain embodiments, said bi-dose device is actuatable with one hand.

In certain embodiments, the delivery time is less than about 30 seconds.In certain embodiments, the delivery time is less than about 25 seconds.In certain embodiments, the delivery time is less than about 20 seconds.In certain embodiments, the delivery time is less than about 15 seconds.

In certain embodiments, the 90% confidence interval for dose deliveredper actuation is ±about 2%. In certain embodiments, the 95% confidenceinterval for dose delivered per actuation is ±about 2.5%.

In certain embodiments, upon nasal delivery of the formulation to thepatient, less than about 20%, less than about 15%, less than about 10%,or less than about 5%, of the formulation leaves the nasal cavity viadrainage into the nasopharynx or externally.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

Indications

Also provided are formulations and devices for use in treatingconditions mediated by adrenergic receptors, and/or one or more symptomsthereof, and methods of treatment of such conditions comprisingadministering the formulations and using the devices disclosed herein.

In certain embodiments, the condition is (1) treatment of acutehypersensitivity, such as a type-1 hypersensitivity reaction (forexample such as an anaphylactoid reaction (systemic allergic reaction)to foods, drugs, animal serums, insect bites and stings, and otherallergens, see below), (2) treatment of acute asthmatic attacks torelieve bronchospasm not controlled by inhalation or subcutaneousadministration of other solutions of the drug, (3) treatment andprophylaxis of cardiac arrest and/or attacks of transitoryatrioventricular (A-V) heart block with syncopal seizures (Stokes-AdamsSyndrome), (4) to increase mean arterial blood pressure in adultpatients with hypotension associated with septic shock, (5) forinduction and maintenance of mydriasis during intraocular surgery.

In certain embodiments, the type-1 hypersensitivity reaction (systemicallergic reaction) is chosen from allergic asthma, allergicconjunctivitis, allergic rhinitis (hay fever), anaphylaxis, angioedema,urticaria (hives), eosinophilia, antibiotic allergy (e.g. to penicillinor cephalosporin), and food allergy (e.g. to peanuts or shellfish).

In certain embodiments, the type-1 hypersensitivity reaction (systemicallergic reaction) is anaphylaxis.

Symptoms of anaphylaxis include hives, generalized itching, nasalcongestion, wheezing, difficulty breathing, cough, cyanosis,lightheadedness, dizziness, confusion, slurred speech, rapid pulse,palpitations, nausea and vomiting, abdominal pain or cramping, skinredness or inflammation, nasal flaring, and intercostal retractions.

In certain embodiments, the symptom of the type-1 hypersensitivityreaction (systemic allergic reaction) is chosen from generalized hives(urticatria), itching (pruritis), flushing, swelling (angioedema) of theafflicted tissues, a burning sensation of the skin (common in those withangioedema), swelling of the tongue or throat, respiratory symptoms suchas shortness of breath, wheezes, or stridor shortness of breath,coronary artery spasm, myocardial infarction, dysrhythmia, or cardiacarrest (those with underlying coronary disease are at greater risk ofcardiac effects), tachycardia, bradycardia, and a Bezold-Jarisch reflex.

In certain embodiments, the type-1 hypersensitivity reaction (systemicallergic reaction) is caused by stinging insects (e.g., orderHymenoptera, which include bees, wasps, hornets, yellow jackets and fireants), biting insects (e.g., triatoma, mosquitoes), allergenimmunotherapy, foods, drugs, diagnostic testing substances (e.g.radiocontrast media) and other allergens, as well as idiopathicanaphylaxis or exercise-induced anaphylaxis.

In certain embodiments, the cardiac arrest is out-of-hospital cardiacarrest.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

EXAMPLES

The following examples are provided for illustrative purposes only andnot to limit the scope of the claims provided herein.

Example 1. Epinephrine Formulations for Clinical Use

A representative procedure for the preparation of formulations forclinical use is described. The Formulation Excipient Solution (FES) canbe made in advance (up to 7 days) and stored at room temperature. Theepinephrine stock solution (ESS) should be made fresh within 72 hours ofdosing, protected from light and excessive oxidation and stored at 2-8°C. until 2 hours before use. A mixture of equal volumes of sterilefiltered FES and ESS will result in a solution of epinephrine,dodecylmaltoside (DDM), EDTA, benzalkonium chloride (BZK) in saline foruse in the clinical protocols below.

A 200 mL batch of Formulation Excipient Solution (FES) is prepared byweighing 0.80 g (0.75-0.85 g) of EDTA into a 200 mL volumetric flask anddissolving in −150 mL of Sterile Saline; weighing 1.00 g (0.95-1.05 g)of Intravail® DDM, quantitatively transferring to the EDTA solution, andmixing until dissolved (solution should be clear and colorless); ifnecessary, using gentle heating (40-60° C.) aid solution, then coolingto room temperature once dissolved; adding the desired amount of a BZKsolution (or adding BZK as a solid) and adding to the mixingIntravail®/EDTA mixture; adding the appropriate amount of 1 N HCl toattain a pH of 4 (e.g. approximately 20 mL), and diluting QS to volumewith Sterile Saline, and stirring until the mixture is uniform. The pHof the FES solution may be measured and recorded.

Epinephrine Stock Solution (ESS) 10 mg/mL should be freshly prepared,protected from light (e.g. with foil, the use of brown colored lights,etc.), and use within 72 hours of dosing. To formulate a 100 mL batch offinal 10 mg/mL product: ensure 100 mL volumetric flask is wrapped infoil prior to adding FES Solution; add 50 mL of FES Solution to each oftwo foil wrapped 100 mL flasks (50 mL per flask); weigh and add 1.0 g(0.95-1.05 g) of epinephrine (E4250 Sigma Aldrich) into each of the two100 mL flasks; mix each until uniform; measure the pH of each flask andrecord.

Final Dosing Formulations (FDF) are prepared by filling appropriatesprayers capable of delivering 100 μL per spray with appropriate amountsof ESS (e.g. about 5.0 mL of ESS for Aptar multi-dose spray devices orabout 125 μL of ESS for uni-dose spray devices).

Representative epinephrine formulations for clinical use are presentedin Table 2, Table 3, and Table 4.

TABLE 2 Representative Epinephrine Formulations for Clinical Use.Ingredients Quantity per mL (−)-Epinephrine 3 5 10 10 10 20 USP (mg) DDM(mg) 2.5 2.5 2.5 2.5 2.5 2.5 Disodium EDTA 2.0 2.0 2.0 2.0 2.0 2.0 USP(mg) BZK USP (mg) 0.1 0.2 0.2 0.4 0.6 0.2 Sodium chloride 8.23 8.23 8.238.23 8.23 8.23 USP (mg) 1 N HCl (mL) 0.051 0.051 0.051 0.051 0.051 0.0510.1 N HCl and/or Adjust to Adjust to Adjust to Adjust to Adjust toAdjust to 0.1 NaOH pH 3.8-4.2 pH 3.8-4.2 pH 3.8-4.2 pH 3.8-4.2 pH3.8-4.2 pH 3.8-4.2 Purified water, QS to 1 QS to 1 QS to 1 QS to 1 QS to1 QS to 1 Millipore, Type I mL mL mL mL mL mL

TABLE 3 Representative Epinephrine Formulations for Clinical Use.Ingredients Quantity per mL (−)-Epinephrine USP 3 5 6.5 10 13 15 20 (mg)DDM (mg) 2.5 2.5 2.5 2.5 2.5 2.5 2.5 Disodium EDTA 2.0 2.0 2.0 2.0 2.02.0 2.0 USP (mg) BZK USP (mg) 0.4 0.4 0.4 0.4 0.4 0.4 0.4 Sodiumchloride 8.23 8.23 8.23 8.23 8.23 8.23 8.23 USP (mg) 1 N HCl (mL) 0.0510.051 0.051 0.051 0.051 0.051 0.051 0.1 N HCl and/or Adjust AdjustAdjust Adjust Adjust Adjust Adjust 0.1 NaOH to pH to pH to pH to pH topH to pH to pH 3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2Purified water, QS to 1 QS to 1 QS to 1 QS to 1 QS to 1 QS to 1 QS to 1Millipore, Type I mL mL mL mL mL mL mL

TABLE 4 Representative Epinephrine Formulations for Clinical Use.Ingredients Quantity per mL (−)-Epinephrine USP 10 10 10 10 10 10 10 10(mg) Dodecylmaltoside 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 (DDM) (mg)Disodium EDTA USP 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 (mg) Benzalkonium 0.40.4 0.4 0.4 0.4 0.4 0.4 0.4 Chloride USP (mg) Sodium chloride USP 8.238.23 8.23 8.23 8.23 8.23 8.23 8.23 (mg) Butylated — 0.1 0.1 — — — — —hydroxyanisole (BHA) (mg) Citric acid — — 0.42 — 4.2 — 4.2 — monohydrate(mg) Isoascorbic Acid (mg) — — — 0.1 0.1 — — D-α-Tocopherol — — — — —5.0 5.0 — polyethylene glycol 1000 succinate (mg) Sodium metabisulfite —— — — — — — 0.05 (mg) 1 NHCl 0.051 mL 0.051 mL 0.051 mL 0.051 mL 0.051mL 0.051 mL 0.051 mL 0.051 mL 0.1 N HCl Adjust Adjust Adjust AdjustAdjust Adjust Adjust Adjust to pH to pH to pH to pH to pH to pH to pH topH 3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2 0.1NaOH Adjust Adjust Adjust Adjust Adjust Adjust Adjust Adjust to pH to pHto pH to pH to pH to pH to pH to pH 3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.23.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2 Purified water, QS to QS to QS to QS toQS to QS to 1 QS to QS to Millipore, Type I 1 mL 1 mL 1 mL 1 mL 1 mL mL1 mL 1 mL

Example 2: Clinical Protocols

The following clinical protocols were carried out, or may be carriedout, in healthy human volunteers to assess the safety, optimal dosing,and pharmacokinetics of intranasal epinephrine.

Example 2A: First Clinical Study

Objective. The primary objective of this study was to assess thecomparative bioavailability of epinephrine after intranasaladministration and intramuscular administration as intramuscularepinephrine delivered by auto injector in healthy volunteers underfasted conditions. A secondary objective was to evaluate the safety andtolerability of intranasal (IN) epinephrine in healthy volunteers.

Study Design. A Phase 1, open-label, randomized, single-dose,two-treatment, crossover study was carried out that consisted of ascreening period, baseline period, and an open-label treatment period.In the screening period, subjects underwent screening within 21 daysprior to entering into the open-label treatment phase of the study. Inthe baseline period, within 24 hours of dosing, initial assessments weretaken; in some cases, screening and baseline visits could be combined ifall assessments are done within 24 hours of dosing.

In the Open-Label Treatment Period, twelve (12) eligible subjects wererandomized after an overnight fast to receive single 0.3 mg doses ofintranasal epinephrine and intramuscular epinephrine delivered by autoinjector. Blood samples were collected for 360 minutes after dosing.Treatments were separated by a minimum 24 hours wash out period. Safetyassessments were performed on each study day and subjects released afterdischarge assessments on Day 1. Subjects were followed for 6 hours afterthe administration of the last dose of study drug.

Plasma samples from all subjects that completed two periods of the studywere analyzed. Blood samples for the measurement of plasmaconcentrations of epinephrine, norepinephrine and dihydroxyphenylglycol(DHPG) (metabolite) were collected before (0, pre-dose) and at 2, 4, 6,8, 10, 12.5, 15, 20, 25, 45, 60, 90, 120, 150, 180, 240 and 360 minutesafter dosing. Actual blood collection times can vary as follows: 1) ±1minutes for the 2 to 20 minute samples, 2) ±2 minutes for the 25 to 90minute samples, and 3) ±5 minutes for the 120 to 360 minute samples.Actual sampling times were recorded.

Study Drugs and Administration. Each 100 μL IN dose of intranasalepinephrine formulation contained, in addition to 0.3 mg epinephrine,0.25% (w/v) dodecylmaltoside (0.25 mg), 0.04% (w/v) benzalkoniumchloride (BZK) (0.04 mg), ethylenediaminetetraacetic acid (EDTA) in 10mM pH 4.0 acetate buffer. The intramuscular epinephrine delivered byauto injector delivered 0.3 mg epinephrine by intramuscular injection.

Subjects were fasted prior to administration of either IN or IMepinephrine. Each 100 μL spray was administered to the left nostril viaa commercially-available multiple dose nasal spray device marketed byAptar Pharma. Priming of the device (activation 5 times) was done in ahood or priming box within 30 minutes prior to dosing the subject.

Participants. The study included healthy male adult volunteers (up to12) between the ages of 18 and 55 years, inclusive, who gave written,informed consent. Other inclusion criteria included: body weight morethan 50 kg; mass index between 18 and 28 kg/(height in m)² (BMI),inclusive; no medical history of hypertension and cardiovasculardisease; blood pressure and heart rate within normal range at screeningand baseline; no clinically significant abnormal findings in medicalhistory, on physical examination, electrocardiogram (QTcF<450 msec), orclinical laboratory results during screening; and agreement to remainconfined in house until study end and willing to comply with allrequired study procedures.

Exclusion criteria included: history of clinically significantgastrointestinal, renal, hepatic, neurologic, hematologic, endocrine,oncologic, respiratory, immunologic, psychiatric, or cardiovasculardisease, severe seasonal or non-seasonal allergies, nasal polyps, nonasal piercings, or any nasal passage abnormality that could interferewith nasal spray administration, or any other condition which, in theopinion of the Principal Investigator, would jeopardize the safety ofthe subject or impact the validity of the study results; smoked within 6months prior to screening; significant traumatic injury, major surgeryor open biopsy within 30 days prior to study screening; history ofallergic or adverse responses to epinephrine or any comparable orsimilar product; an abnormal diet (such as one that severely restrictsspecific basic food groups [e.g., ketogenic diet], limits calories[e.g., fast], and/or requires the use of daily supplements as asubstitute for the foods typically eaten at mealtimes), during the four(4) weeks preceding the study; donation of blood or plasma within 30days of the first dose of study drug; participation in a clinical trialwithin 30 days prior to the first dose of study drug (non-interventionaltrial acceptable); inadequate or difficult venous access that couldjeopardize the quality or timing of the PK samples; positive bloodscreen for HIV, Hepatitis B surface antigen (HbSAg), or Hepatitis C, ora positive urine screen for alcohol (saliva test may be utilized atbaseline), drugs of abuse, or cotinine.

Additionally, during the study, subjects were not permitted: to take OTCproducts, including vitamins and supplements, for the seven (7) dayspreceding the study; to use any prescription medication within 14 daysprior to the first dose of study drug or during the study unlessapproved by the Principal Investigator and medical monitor; to use oraland/or nasal decongestants within 14 days prior to the first dose ofstudy drug or during the study; to smoke or use tobacco products for six(6) months prior to the first dose of Study Drug and for the duration ofthe study; or to engage in strenuous exercise during the confinementperiod of the study.

Safety. Adverse events were collected and reviewed to evaluate thesafety and tolerability of intranasal (IN) epinephrine. Other safetymeasures included vital sign measurement. Objective evaluations of nasalirritation were assessed after each administration of study drug using a6-point (0→5) score. The scoring was done by a trained observer based onan assessment of the nasal mucosa prior to dosing (baseline) and at 30(±5 min) minutes, and 1 (±10 min), 2 (±15 min), 4 (±30 min), and 6 (±30min) hours post dose. Irritation was assessed by evaluating the degreeof mucosal inflammation and bleeding. The subjects were required toreport any incident of bleeding or inflammation in-between the actualevaluation time points.

An unconstrained visual analog scale (VAS) that consists of a 10 cm (100mm) horizontal straight line was used to assess acute pain followingeach administration of the intranasal intranasal (IN) epinephrine drugproduct. The ends of the scale were defined as extreme limits of painsensation: 0=no pain, 10=extreme pain. The subjects were asked to mark apoint on the scale which best describes their intensity of pain anddiscomfort just prior to dosing (baseline) and at 15 (±2 min) and 30 (±5min) minutes, and 1 (±10 min) hour post dose. The location of themarking at each time point was measured and noted as the reported score.

Pharmacokinetic Analysis. Pharmacokinetic parameters for epinephrine,norepinephrine and DHPG will be calculated using non-compartmentalanalysis were calculated: maximum plasma concentration (C_(max)), timeto C_(max) (t_(max)), area under the curve to the final time with aconcentration equal to or greater than the lower limit of quantitation[AUC_((0-t))] and to infinity [AUC_((inf))], elimination rate constant(λz) and half-life (t½), and, for epinephrine only, clearance (CL/F) andvolume of distribution (Vz/F) uncorrected for bioavailability (F).

Non-GCP pharmacokinetic analysis was performed using WinNonlin version7.0. The lower limit of bioanalytical quantification was 20 pg/mL.Plasma concentration designated as BLQ were given a value of 20 pg/mL.The pharmacokinetic parameters C_(max), AUC_((0-t)), and AUC_((inf)) forepinephrine, norepinephrine and DHPG were compared among treatmentsusing an analysis of variance (ANOVA) model with treatment, period,sequence, and subject within sequence as the classification variablesusing the natural logarithms of the data. Baseline corrected C_(max) wascalculated from the uncorrected C_(max)—PreDose concentration. Baselinecorrected AUC_(0-t) was calculated from the uncorrectedAUC_(0-t)—PreDose concentration×t_(last). Confidence intervals (90%)were constructed for the geometric mean ratios,intranasal-to-intramuscular epinephrine of the three parameters usingthe log-transformed data and the two one-sided t-tests procedure. Thepoint estimates and confidence limits will be exponentiated back to theoriginal scale. Comparability between intranasal (IN) epinephrine andintramuscular epinephrine was assessed from the geometric mean ratiosand 90% confidence intervals for the three parameters.

Results. Mean plasma concentration of epinephrine from IN administrationremained significantly below that of epinephrine from intramuscularepinephrine delivered by auto injector throughout the study, as shown inFIG. 3 . Intranasal administration of epinephrine using the aboveintranasal epinephrine formulation resulted in significantly lowerexposure (C_(max) and AUC_(0-t)) of the parent compound epinephrinecompared to intramuscular epinephrine delivered by auto injector, asshown below in Table 5. There were no related adverse events reported.The pH was between 3 and 4.

TABLE 5 Intramuscular and Intranasal Administraton of Epinephrine.Intramuscular 0.3 mg Intranasal 0.3 mg C_(max) AUC_(0-t) t_(max) C_(max)AUC_(0-t) t_(max) (pg/mL) (hr*pg/mL) (min) (pg/mL) (hr*pg/mL) (min) Mean333 19878 18 83 8932 53 SD 196 6051 53 6385 Min 71 7493 6 19 767 2Median 311 19606 20 83 7771 23 Max 729 30381 45 222 23011 240 CV % 59 3064 71 Geometric Mean 280 18854 69 6619 CV % Geometric 72 38 73 117 Mean

Example 2B: Second Clinical Study

Objective. The primary objectives of this study were to determine theoptimal dose of a formulation of intranasal epinephrine (IN-Epi) to beused in a study of, and in that study to assess, the comparativebioavailability of epinephrine after intranasal administration andintramuscular administration by injection (EpiPen®) injection in healthyvolunteers under fasted conditions. A secondary objective was toevaluate the safety and tolerability of the formulation of intranasalepinephrine in healthy volunteers.

Study Design. A Phase 1, dose escalation followed by a 12 subjectopen-label, randomized, single-dose, two-treatment, two-period,crossover studies was conducted as follows.

A dose escalation in three subjects was conducted to determine theoptimal dose of epinephrine. In the Screening Period, subjects underwentscreening within 28 days prior to entering into the study. Three (3)subjects were subsequently enrolled and received IN-Epi doses of 0.5 mg,1.0 mg and 2.0 mg epinephrine by IN administration (formulated at pH 5.5to 6.0) after an overnight fast. Blood samples were collected for 360minutes after dosing. Treatments were separated by a minimum 24 hourswash out period.

Thereafter, comparative bioavailabilty of the intranasal formulation tointramuscular injection was assessed in twelve subjects in anopen-label, randomized, single-dose, two-treatment, two-period,crossover study that consisted of a screening period, baseline period,and an open-label treatment period. In the Screening Period, subjectsunderwent screening within 28 days prior to entering into the study. Inthe Open-Label Treatment Period, twelve (12) eligible subjects wererandomized to 1.0 mg of IN-Epi or a 0.3 mg dose of epinephrine injectionby IM administration (EpiPen®) after an overnight fast to receive singledoses. Blood samples are collected for 360 minutes after dosing.Treatments are separated by a minimum 24 hours wash out period.

Safety assessments were performed at each of the study day and subjectscould be released after discharge assessment. Subjects were followed for6 hours after the administration of the last dose of study drug.

The study was carried out in part as disclosed above. For all parts ofthe study, the following procedures were performed as follows.

Study Drugs and Administration. Each 100 μL IN dose of epinephrineformulation contained, in addition to 0.5 mg, 1.0 mg, or 2.0 mg (5mg/mL, 10 mg/mL, or 20 mg/mL) of IN-Epi, 0.25% (w/v) dodecylmaltoside(0.25 mg), 0.04% (w/v) benzalkonium chloride (BZK) (0.04 mg), andEthylenediaminetetraacetic acid (EDTA) in 0.9% (w/v) saline, at pH 4.5(3.5 to 5.0). The commercially available EpiPen® delivers 0.3 mgepinephrine by intramuscular injection.

Subjects were fasted prior to administration of either IN or IMepinephrine. Each 100 μL spray was administered to the left nostril viaa commercially-available multiple dose nasal spray device marketed byAptar Pharma. Priming of the device (activation 5 times) was done in ahood or priming box within 30 minutes prior to dosing the subject.

Participants. A total of fifteen (15) males were enrolled in the study.Plasma samples from all subjects that complete the study were analyzed.Blood samples for the measurement of plasma concentrations ofepinephrine were collected before (0, pre-dose) and at 2, 4, 6, 8, 10,12.5, 15, 20, 25, 45, 60, 90, 120, 150, 180, 240 and 360 minutes afterdosing. Actual blood collection times could vary as follows: 1) ±1minutes for the 2 to 20 minute samples, 2) ±2 minutes for the 25 to 90minute samples, and 3) ±5 minutes for the 120 to 360 minute samples.

Inclusion criteria. Participants: were male, between ages 18 and 30,inclusive; gave written informed consent; had body weight more than 50kg and mass index between 18 and 28 kg/m2, inclusive; had nofamily/medical history of hypertension and cardiovascular disease withinthe past 10 years; have blood pressure within normal range (i.e. <140/90mmHg) at screening; had no clinically significant abnormal findings inthe medical history, on physical examination, electrocardiogram(QTcF<450 msec), or clinical laboratory results during screening; andagreed to remain confined in house during appropriate study times andwilling to comply with all required study procedures.

Exclusion Criteria. Exclusion criteria included history of clinicallysignificant gastrointestinal, renal, hepatic, neurologic, hematologic,endocrine, oncologic, pulmonary, immunologic, psychiatric, orcardiovascular disease, severe seasonal or non seasonal allergies, nasalpolyps, or any nasal passage abnormality that could interfere with nasalspray administration, or any other condition which, in the opinion ofthe Principal Investigator, would jeopardize the safety of the subjector impact the validity of the study results; had smoked within 6 monthsprior to screening; significant traumatic injury, major surgery or openbiopsy within 30 days prior to study screening; history of allergic oradverse responses to epinephrine or any comparable or similar product;had been on an abnormal diet (such as one that severely restrictsspecific basic food groups [e.g., ketogenic diet], limits calories[e.g., fast], and/or required the use of daily supplements as asubstitute for the foods typically eaten at mealtimes), during the four(4) weeks preceding the study; donated blood or plasma within 30 days ofthe first dose of study drug; participation in a clinical trial within30 days prior to the first dose of study drug; inadequate or difficultvenous access that may jeopardize the quality or timing of the PKsamples; positive blood screen for HIV, Hepatitis B surface antigen(HbSAg), or Hepatitis C, or a positive urine screen for alcohol, drugsof abuse, or cotinine.

Additionally, during the study, subjects were not permitted: to take OTCproducts, including vitamins and supplements, for the seven (7) dayspreceding the study; to use any prescription medication within 14 daysprior to the first dose of study drug or during the study unlessapproved by the Principal Investigator and medical monitor; to use oraland/or nasal decongestants within 14 days prior to the first dose ofstudy drug or during the study; to smoke or use tobacco products for six(6) months prior to the first dose of Study Drug and for the duration ofthe study; or to engage in strenuous exercise during the confinementperiod of the study.

Safety. Adverse events were collected and were or will be reviewed toevaluate the safety and tolerability of IN-Epi. Other safety measureswill include vital sign measurements.

Objective evaluations of nasal irritation were assessed after eachadministration of study drug using a 6-point (0→5) score. The scoringwas done by a medically trained observer based on an assessment of thenasal mucosa prior to dosing (baseline) and at 30 (±5 min) minutes, and1 (±10 min), 2 (±15 min), 4 (±30 min), and 6 (±30 min) hours post dose.Irritation was assessed by evaluating the degree of mucosal inflammationand bleeding. Subjects were also required to report any incident ofbleeding or inflammation in-between the actual evaluation time points.

An unconstrained visual analog scale (VAS) that consists of a 10 cm (100mm) horizontal straight line was used to assess acute pain followingeach administration of the IN-Epi drug product. The ends of the scalewere defined as extreme limits of pain sensation: 0=no pain, 10=extremepain. Subjects were asked to mark a point on the scale which bestdescribes their intensity of pain and discomfort just prior to dosing(baseline) and at 15 (±2 min) and 30 (±5 min) minutes, and 1 (±10 min)hour post dose. The location of the marking at each time point wasmeasured and noted as the reported score.

Pharmacokinetic Analysis. Pharmacokinetic parameters for epinephrinewere calculated using non-compartmental analysis: maximum plasmaconcentration (C_(max)), time to C_(max) (t_(max)), area under the curveto the final time with a concentration equal to or greater than thelower limit of quantitation [AUC_((0-t))] and to infinity [AUC_((inf))],elimination rate constant (λz) and half-life (t½), and, for epinephrineonly, clearance (CL/F) and volume of distribution (Vz/F) uncorrected forbioavailability (F).

Pharmacokinetic parameters C_(max), AUC_((0-t)), and AUC_((inf)) forepinephrine were compared among treatments using an analysis of variance(ANOVA) model with treatment, period, sequence, and subject withinsequence as the classification variables using the natural logarithms ofthe data. Confidence intervals (90%) were constructed for the geometricmean ratios, IN-Epi-to-EpiPen®, of the three parameters using thelog-transformed data and the two one-sided t-tests procedure. The pointestimates and confidence limits were exponentiated back to the originalscale. Comparability between IN and IM epinephrine were assessed fromthe geometric mean ratios and 90% confidence intervals for the threeparameters.

Results. Results for the dose escalation portion of the study are givenbelow in Table 6 and in FIGS. 4, 5, 6, and 7 . Intranasal formulationsof epinephrine formulated as disclosed above at doses of 0.5, 1.0, and2.0 mg in saline at pH 4.0 (3.5-5.0 acceptable) were administered tothree subjects. Table 6 below gives the mean pharmacokinetic parametersfor the three doses.

TABLE 6 Mean pharmacokinetic parameters for three doses of intranasalepinephrine. 0.5 mg 1.0 mg 2.0 mg AUC_(0-t) AUC_(0-t) AUC_(0-t) t_(max)C_(max) (min* t_(max) C_(max) (min* t_(max) C_(max) (min* (min) (pg/mL)pg/mL) (min) (pg/mL) pg/mL) (min) (pg/mL) pg/mL) Mean 28.3 234 2400012.7 586 43900 12.5 2470 166000 SD 27.4 22.4 5090 6.43 369 18400 2.51370 80800 CV % 96.8 9.55 21.2 50.8 63 41.8 20 55.4 48.7 Geo Mean 21.1234 23600 11.7 468 41100 12.3 2230 154000

As can be seen, T_(max) was lower, and C_(max) and AUC higher, for alldoses of intranasal epinephrine than in the previous study. These trendswere more marked with increasing dose. In particular, the 1.0 and 2.0 mgformulations each exhibited a T_(max) that was lower than intramuscularepinephrine delivered by auto injector as used in the previous study,and a C_(max) that was higher. AUC for all intranasal formulations washigher than for intramuscular epinephrine delivered by auto injector forall doses.

FIGS. 4 and 5 show the mean time-vs-concentration curves for the 0.5,1.0, and 2.0 mg intranasal formulations of epinephrine. FIGS. 6 and 7duplicate the data in FIGS. 4 and 5 , but overlay it on the epinephrineauto injector data from Study 2A to illustrate the pharmacokineticdifferences between, for example, the 1.0 and 2.0 mg intranasal doses ofepinephrine and intramuscular epinephrine auto injector. These figuresalso provide a relevant contrast to FIG. 3 , where intranasalepinephrine was formulated in acetate buffer at pH 3-4.

The results from the dose escalation portion of the study show, incontrast to previous studies, that epinephrine can be formulated toachieve significant bioavailability. At certain doses, thepharmacokinetics of intranasal epinephrine so formulated appearssuperior to intramuscular epinephrine delivered by auto injector,achieving a rapid, IM-injection-like rate of absorption in the first 20minutes.

Results for the portion of the study comparing bioavailability of IN toIM injection are given below in Tables 7-9c and in FIGS. 8 and 9 .Intranasal epinephrine formulated as disclosed above at a dose of 1.0 mgin saline at approximately pH 4.0 was administered to twelve subjects; afurther twelve were administered intramuscular epinephrine delivered byauto injector (0.3 mg) in the thigh. Table 7 below shows mean PKparameters for IN and IM epinephrine formulated as disclosed above.

TABLE 7 Mean PK parameters for IN and IM epinephrine. Intranasal 1.0 mgIM Injection Thigh 0.3 mg C_(max) AUC_(0-t) t_(max) C_(max) AUC_(0-t)t_(max) (pg/mL) (min*pg/mL) (min) (pg/mL) (min*pg/mL) (min) N 12 12 1212 12 12 Min 182 28102 6 64 16318 20 Max 484 70450 150 560 66792 61 GeoMean 305 44221 25 236 45294 25 CV % Geo Mean 30 28 161 64 48 183

FIGS. 8 and 9 also demonstrate that the plasma time vs. concentrationcurve for 1.0 mg IN epinephrine is very similar to that for 0.3 mg. IMepinephrine (EpiPen®) administered in the thigh.

Table 8 below shows C_(max) and partial AUC data comparing the IM and INroutes. Ratio of intranasal as a percent of reference for AUCs aregiven. The data below demonstrate that 1.0 mg intranasal epinephrine canbe formulated to be highly similar to or better than a 0.3 mgintramuscular injection of epinephrine.

TABLE 8 Comparison of Key Pharmacokinetic Parameters between Intranasaland Intramuscular Administration—Ratio Defined asIntranasal/Intramuscular with 90% Confidence Interval. 90% ConfidenceInterval Dependent Ratio % Ref Lower Upper C_(max) 129 90 185 AUC_(0-t)98 78 122 AUC_(0-21/2) 85 60 120 AUC₀₋₅ 74 50 109 AUC_(0-71/2) 73 46 116AUC₀₋₁₀ 79 48 130 AUC₀₋₁₅ 93 57 150 AUC₀₋₂₀ 102 64 163

Tables 9a-9c below show comparisons of 9a) the median t_(max), 9b) thedistribution of t_(max) values, and 9c) the percent of subjects witht_(max) satisfying the stated condition between intranasal andintramuscular epinephrine.

TABLE 9a Distribution of tmax Values Resulting After Intranasal andIntramuscular Administration. t_(max) (minutes) Percentile IntranasalIntramuscular 25% 9 6 Median (50%) 20 35 75% 79 60

TABLE 9b t_(max) Values Listed in Ascending Order After Intranasal andIntramuscular Administration. Intranasal Intramuscular t_(max) (minutes)6 4 8 6 8 6 9 6 10 6 20 25 20 25 20 35 20 45 20 60 45 60 79 60

TABLE 9c Percent of Subjects with t_(max) Satisfying Stated ConditionAfter Intranasal and Intramuscular Administration. Percent of SubjectsNumber of Subjects Intra- Intra- Intra- Intra- t_(max) Condition (Min.)nasal muscular nasal muscular Less than 40 min. 83%  67% 10 8 Less than35 min. 83%  58% 10 7 Between 30 and 8% 17% 1 2 45 min. Between 30 and0%  8% 0 1 40 min. Between 30 and 0%  8% 0 1 35 min.

IN-Epi appeared to be safe and well-tolerated, and demonstrated PKparameters equivalent to and in some aspects (e.g. C_(max)) are betterthan epinephrine auto injector.

Additionally, throughout the study, no significant PK differences wereobserved between 1.0 mg IN epinephrine and the 0.3 mg. IM epinephrine.

OTHER EMBODIMENTS

Also provided are embodiments wherein any embodiment above can becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive. Also provided herein are uses inthe treatment of indications or one or more symptoms thereof asdisclosed herein, and uses in the manufacture of medicaments for thetreatment of indications or one or more symptoms thereof as disclosedherein, equivalent in scope to any embodiment disclosed above, or anycombination thereof that is not mutually exclusive. The methods and usesmay employ any of the devices disclosed herein, or any combinationthereof that is not mutually exclusive, or any of the pharmaceuticalformulations disclosed herein, or any combination thereof that is notmutually exclusive.

Although the present invention has been described with reference tospecific details of certain embodiments thereof in the above examples,it will be understood that modifications and variations are encompassedwithin the spirit and scope of the invention.

What is claimed is:
 1. A method of treating a type-1 hypersensitivityreaction in a human comprising an intranasal administration of a nasalspray pharmaceutical formulation to the human with a type-1hypersensitivity reaction, wherein a single intranasally administereddose of the nasal spray pharmaceutical formulation comprises: a) between0.1 mg and 2.4 mg of epinephrine, wherein epinephrine is the onlypharmaceutically active ingredient in the nasal spray pharmaceuticalformulation; b) one or more other agents as excipients selected from thegroup consisting of: absorption enhancement agents, isotonicity agents,stabilizing agents, antioxidants, preservatives, and pH adjustmentagents; and c) water; wherein the nasal spray pharmaceutical formulationhas a pH between about 3.0 and about 5.0; wherein the volume of thesingle intranasally administered dose of the nasal spray pharmaceuticalformulation is between 25 μL and 250 μL; wherein the intranasaladministration of the nasal spray pharmaceutical formulation to thehuman with the type-1 hypersensitivity reaction provides plasmaepinephrine concentrations in the human that are efficacious for theelimination of one, more than one, or all of the symptoms of the type 1hypersensitivity reaction in the human; or wherein the intranasaladministration of the nasal spray pharmaceutical formulation to thehuman with the type-1 hypersensitivity reaction provides plasmaepinephrine concentrations in the human that are efficacious for theprevention of the further progression of one, more than one, or all ofthe symptoms of the type 1 hypersensitivity reaction in the human. 2.The method of claim 1, wherein the symptoms of the type-1hypersensitivity reaction comprise: generalized hives, pruritis,flushing, angioedema, a burning sensation of the skin, swelling of thetongue or throat, shortness of breath, wheezes, stridor, coronary arteryspasm, myocardial infarction, dysrhythmia, cardiac arrest, tachycardia,bradycardia, a Bezold-Jarisch reflex, or combinations thereof.
 3. Themethod of claim 1, wherein the type-1 hypersensitivity reactioncomprises allergic asthma, allergic conjunctivitis, allergic rhinitis,anaphylaxis, angioedema, urticaria, eosinophilia, or combinationsthereof.
 4. The method of claim 1, wherein the type-1 hypersensitivityreaction comprises anaphylaxis.
 5. The method of claim 1, wherein thetype-1 hypersensitivity reaction comprises anaphylaxis; and the symptomsof anaphylaxis are selected from the group consisting of hives,generalized itching, nasal congestion, wheezing, difficulty breathing,cough, cyanosis, lightheadedness, dizziness, confusion, slurred speech,rapid pulse, palpitations, nausea and vomiting, abdominal pain orcramping, skin redness or skin inflammation, nasal flaring, andintercostal retractions.
 6. The method of claim 1, wherein the singleintranasally administered dose of the nasal spray pharmaceuticalformulation comprises about 0.5 mg, about 0.6 mg, about 0.7 mg, about0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about2.3 mg, or about 2.4 mg, in a volume of about 100 μL.
 7. The method ofclaim 4, wherein a single intranasally administered dose of the nasalspray pharmaceutical formulation comprises about 0.3 mg, about 0.5 mg,about 1.0 mg, or about 2.0 mg of epinephrine.
 8. The method of claim 1,wherein the single intranasally administered dose of the nasal spraypharmaceutical formulation comprises about 1.0 mg of epinephrine.
 9. Themethod of claim 1, wherein the single intranasally administered dose ofthe nasal spray pharmaceutical formulation comprises about 2.0 mg ofepinephrine.
 10. The method of claim 1, wherein: the absorptionenhancement agents are selected from the group consisting ofsurfactants, fatty acids, bile salts, cyclodextrins, phospholipids, andalcohols; the isotonicity agents are selected from the group consistingof dextrose, glycerin, mannitol, potassium chloride, and sodiumchloride; the antioxidants are selected from the group consisting ofalpha tocopherol, D-α-tocopherol polyethylene glycol 1000 succinate,ascorbic acid, isoascorbic acid, butylated hydroxyanisole, citric acidmonohydrate, potassium metabisulfite, sodium bisulfate, sodiummetabisulfite, and sodium sulfite.
 11. The method of claim 1, wherein:the absorption enhancement agents are selected from the group consistingof dodecyl maltoside, polysorbate 20, polysorbate 80, oleic acid, sodiumlauryl sulfate, sodium glycocholate, sodium taurocholate, and sodiumtaurodihydrofusidate; the isotonicity agents are selected from the groupconsisting of dextrose, glycerin, mannitol, potassium chloride, andsodium chloride; the antioxidants are selected from the group consistingof alpha tocopherol, D-α-tocopherol polyethylene glycol 1000 succinate,ascorbic acid, isoascorbic acid, butylated hydroxyanisole, citric acidmonohydrate, potassium metabisulfite, sodium bisulfate, sodiummetabisulfite, and sodium sulfite.
 12. The method of claim 11, whereinthe stabilizing agent is ethylenediaminetetraacetic acid (EDTA) ordisodium salt thereof; and the preservative is benzalkonium chloride.13. The formulation of claim 12, wherein the pH adjustment agents areselected from the group consisting of adipic acid, ammonium chloride,citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoricacid, propionic acid, sulfuric acid, tartaric acid, sodium hydroxide,sodium citrate, sodium bicarbonate, and sodium carbonate.
 14. The methodof claim 13, wherein the volume of the single intranasally administereddose of the nasal spray pharmaceutical formulation is about 50 μL, about75 μL, about 100 μL, about 125 μL, about 150 μL, about 175 μL, about 200μL, or about 250 μL.
 15. The method of claim 9, wherein the volume ofthe single intranasally administered dose of the nasal spraypharmaceutical formulation is about 100 μL.
 16. A method of treating atype-1 hypersensitivity reaction in a human comprising an intranasaladministration of a nasal spray pharmaceutical formulation to the humanwith the type-1 hypersensitivity reaction, wherein a single intranasallyadministered dose of the nasal spray pharmaceutical formulationcomprises: a) comprises about 0.5 mg, about 0.6 mg, about 0.7 mg, about0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about2.3 mg, about 2.4 mg, or about 2.5 mg of epinephrine in a volume ofabout 100 μL, wherein epinephrine is the only pharmaceutically activeingredient in the nasal spray pharmaceutical formulation; b) one or moreabsorption enhancement agents as excipients selected from the groupconsisting of surfactants, fatty acids, bile salts, cyclodextrins,phospholipids, and alcohols; c) one or more isotonicity agents asexcipients selected from the group consisting of dextrose, glycerin,mannitol, potassium chloride, and sodium chloride; and d) water; whereinthe nasal spray pharmaceutical formulation has a pH between about 3.0and about 5.0; wherein the type-1 hypersensitivity reaction comprisesanaphylaxis; wherein the intranasal administration of the nasal spraypharmaceutical formulation to the human with the type-1 hypersensitivityreaction provides plasma epinephrine concentrations in the human thatare efficacious for the elimination of one, more than one, or all of thesymptoms of the type 1 hypersensitivity reaction in the human; orwherein the intranasal administration of the nasal spray pharmaceuticalformulation to the human with the type-1 hypersensitivity reactionprovides plasma epinephrine concentrations in the human that areefficacious for the prevention of the further progression of one, morethan one, or all of the symptoms of the type 1 hypersensitivity reactionin the human.
 17. The method of claim 16, wherein the absorptionenhancement agents are selected from the group consisting of dodecylmaltoside, polysorbate 20, polysorbate 80, oleic acid, sodium laurylsulfate, sodium glycocholate, sodium taurocholate, and sodiumtaurodihydrofusidate.
 18. The method of claim 16, wherein thepharmaceutical formulation further comprises one or more antioxidants asexcipients selected from the group consisting of alpha tocopherol,D-α-tocopherol polyethylene glycol 1000 succinate, ascorbic acid,isoascorbic acid, butylated hydroxyanisole (BHA), citric acidmonohydrate, potassium metabisulfite, sodium bisulfite, sodiummetabisulfite, and sodium sulfite.
 19. The method of claim 16, whereinthe pharmaceutical formulation further comprisesethylenediaminetetraacetic acid (EDTA) or disodium salt thereof, andbenzalkonium chloride as excipients.
 20. The method of claim 16, whereinthe pharmaceutical formulation further comprises one or more pHadjustment agents as excipients selected from the group consisting ofadipic acid, ammonium chloride, citric acid, acetic acid, hydrochloricacid, lactic acid, phosphoric acid, propionic acid, sulfuric acid,tartaric acid, sodium hydroxide, sodium citrate, sodium bicarbonate, andsodium carbonate.
 21. The method of claim 16, wherein the pharmaceuticalformulation further comprises one or more pH adjustment agents asexcipients selected from the group consisting of hydrochloric acid andsodium hydroxide.
 22. A method of treating a type-1 hypersensitivityreaction in a human comprising an intranasal administration of a nasalspray pharmaceutical formulation to the human with the type-1hypersensitivity reaction, wherein a single intranasally administereddose of the nasal spray pharmaceutical formulation comprises: a) betweenabout 0.4 mg and about 2.4 mg of epinephrine, and wherein epinephrine isthe only pharmaceutically active ingredient in the nasal spraypharmaceutical formulation; b) one or more absorption enhancement agentsas excipients selected from the group consisting of: surfactants, fattyacids, bile salts, cyclodextrins, phospholipids, and alcohols; and c)water; wherein the nasal spray pharmaceutical formulation has a pHbetween about 3.0 and about 5.0; wherein the total volume of the singleintranasally administered dose of the nasal spray pharmaceuticalformulation is between about 50 μL and about 250 μL; wherein the type-1hypersensitivity reaction comprises anaphylaxis; wherein the intranasaladministration of the nasal spray pharmaceutical formulation to thehuman with the type-1 hypersensitivity reaction provides plasmaepinephrine concentrations in the human that are efficacious for theelimination of one, more than one, or all of the symptoms of the type 1hypersensitivity reaction in the human; or wherein the intranasaladministration of the nasal spray pharmaceutical formulation to thehuman with the type-1 hypersensitivity reaction provides plasmaepinephrine concentrations in the human that are efficacious for theprevention of the further progression of one, more than one, or all ofthe symptoms of the type 1 hypersensitivity reaction in the human. 23.The method of claim 22, wherein the absorption enhancement agents areselected from the group consisting of dodecyl maltoside, polysorbate 20,polysorbate 80, oleic acid, sodium lauryl sulfate, sodium glycocholate,sodium taurocholate, and sodium taurodihydrofusidate.
 24. The method ofclaim 22, wherein the pharmaceutical formulation further comprises: oneor more isotonicity agents as excipients selected from the groupconsisting of dextrose, glycerin, mannitol, potassium chloride, andsodium chloride; one or more antioxidants as excipients selected fromthe group consisting of alpha tocopherol, D-α-tocopherol polyethyleneglycol 1000 succinate, ascorbic acid, isoascorbic acid, butylatedhydroxyanisole (BHA), citric acid monohydrate, potassium metabisulfite,sodium bisulfite, sodium metabisulfite, and sodium sulfite; and one ormore pH adjustment agents as excipients selected from the groupconsisting of adipic acid, ammonium chloride, citric acid, acetic acid,hydrochloric acid, lactic acid, phosphoric acid, propionic acid,sulfuric acid, tartaric acid, sodium hydroxide, sodium citrate, sodiumbicarbonate, and sodium carbonate.
 25. The method of claim 22, whereinthe pharmaceutical formulation further comprisesethylenediaminetetraacetic acid (EDTA) or disodium salt thereof, andbenzalkonium chloride as excipients.
 26. The method of claim 22, whereinthe single intranasally administered dose of the nasal spraypharmaceutical formulation comprises about 0.5 mg, about 1.0 mg, orabout 2.0 mg of epinephrine.
 27. The method of claim 22, wherein thesingle intranasally administered dose of the nasal spray pharmaceuticalformulation comprises about 1.0 mg of epinephrine.
 28. The method ofclaim 22, wherein the single intranasally administered dose of the nasalspray pharmaceutical formulation comprises about 2.0 mg of epinephrine.29. The method of claim 22, wherein the volume of the singleintranasally administered dose of the nasal spray pharmaceuticalformulation is about about 50 μL, about 75 μL, about 100 μL, about 125μL, about 150 μL, about 175 μL, about 200 μL, or about 250 μL.
 30. Themethod of claim 22, wherein the single intranasally administered dose ofthe nasal spray pharmaceutical formulation comprises about 0.5 mg, about0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about2.1 mg, about 2.2 mg, about 2.3 mg, or about 2.4 mg of epinephrine in avolume of about 100 μL.